KR20010085854A - Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors - Google Patents

Abstract

The present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof, wherein R ₁ , G ₁ , G ₂ , R ₄ , Z, X and n are as defined herein, which is an anti-neoplastic in the treatment of cysticosins. Useful as a zero.

Formula 1

Description

SUBSTITUTED 3-CYANOQUINOLINES AS PROTEIN TYROSINE KINASES INHIBITORS As a Protein Tyrosine Kinase Inhibitor

Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups from APT to tyrosine residues located on protein substrates. Protein tyrosine kinases certainly play a role in normal cell growth. Many growth factor receptor proteins function as tyrosine kinases and in this way they perform signaling. Interaction of these factors with growth receptors is a necessary event in the normal regulation of cell growth. However, under certain conditions, as a result of mutation or overexpression, these receptors can be unregulated: the result is unregulated cell proliferation that can lead to tumor growth and ultimately a disease known as cancer [Wilks A. F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J. T .; Parsons, S. J., Important Advances in Oncology, DeVita V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)]. The growth factor receptor kinases and their primitive-tumor genes identified and targeted by the compounds of the invention are epidermal growth factor receptor kinase (EGF-R kinase, protein product of the erbB tumor gene) and erbB-2 (also referred to as neu or HER2) It is a product produced by oncogenes. Because phosphorylation events are the signals necessary for cell division to occur and overexpressed or mutated kinases are associated with cancer, inhibitors of these events, protein tyrosine kinase inhibitors, are used to treat cancer and other diseases characterized by unregulated or abnormal cell growth. To have therapeutic value. For example, overexpression of the receptor kinase product of the erbB-2 tumor gene is associated with human breast cancer and ovarian cancer [Slamon, D. J., et. al., Science, 244, 707 (1989) and Science, 235, 1146 (1987)]. Unregulation of EGF-R kinase has been described in epidermal tumors [Reiss, M., et. al., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anticancer Res., 7, 459 (1987)] and other major organ-related tumors [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)]. Because of the importance of the role played by unregulated receptor kinases in the development of cancer, many recent studies have addressed the development of specific PTK inhibitors as potent anticancer therapies [Recent data: Burke. T. R., Drugs Future, 17, 119 (1992) and Chang, C. J .; Geahlen, R. L., J. Nat. Prod., 55, 1529 (1992). The compounds of the present invention inhibit the kinase activity of EGF-R and are therefore useful for the treatment of certain disease symptoms such as cancer resulting at least in part from unregulation of this receptor. The compounds of the present invention are also useful for the treatment and prevention of certain precancerous conditions, such as the growth of colon sarcoma, resulting at least in part from unregulation of this receptor.

It is also known that deregulation of the EGF receptor is a growth factor of epidermal cysts in the described diseases such as cysticosins [Du J., Wilson P. D., Amer. J. Physiol., 269 (2 Pt 1), 487 (1995); Nauta J., et al., Pediatric Research, 37 (6), 755 (1995); Gattone V. H., et al., Developmental. Biology, 169 (2), 504 (1995); Wilson P. D., et al., Eur. J. Cell Biol., 61 (1), 131, (1993)]. Compounds of the invention which inhibit the catalytic function of the EGF receptor are conclusively useful for the treatment of this disease.

The mitotic substance-activated protein kinase (MAPK) pathway is a major pathway in the cellular signal transduction cascade from growth factors to the cell nucleus. The pathway comprises kinases at two levels: MAP kinase kinase (MAPKK) and its substrate MAP kinase (MAPK). Different isotypes exist for the MAP kinases. (Rony Seger and Edwin G. Krebs, FASEB, Vol. 9, 726, June 1995). Compounds of the invention can inhibit the action of these two kinases: MEK, MAP kinase kinase and its substrates ERK, MAP kinase. MEK is activated by phosphorylation on two serine residues by upstream kinases such as members of the raf family. When activated, MEK catalyzes phosphorylation on threonine and tyrosine residues of ERK. The active ERK is then phosphorylated and activates transcription factors at the nuclear or other cellular targets with PXT / SP sequences such as fos and jun. ERK, p42 MAPK was found to be essential for cell proliferation and differentiation. Overexpression and / or overactivation of Mek or ERK has been found to be associated with various cancers in humans (eg, Vimala S. Sivaraman, Hsien-yu Wang, Gerard J. Nuovo and Craig C. Malbon, J. Clin. Invest. Vol. 99, No. 7 April 1997). It has been described that inhibition of MEK prevents activation of ERK and subsequent activation of ERK substrates in cells, resulting in inhibition of cell growth promotion and induction of ras-transformed cell phenotypes (David T. Dudley, Long Pang, Stuart J). Decker, Alexander J. Bridges and Alan R. Saltiel, PNAS, Vol. 92, 7686, August 1995). As described below, because the compounds of the present invention can inhibit the complex action of MEK and ERK, they are characterized by unregulated cell proliferation and are at least partially involved in the treatment of diseases such as cancer, depending on the MAPK pathway. useful.

Epidermal cell kinase (ECK) is a receptor protein tyrosine kinase (RPTK) belonging to the class of erythropoietin-producing liver cancer (EPH). Although originally identified as epidermal lineage-specific tyrosine kinase, ECK is subsequently shown to be expressed on vascular endothelial cells, smooth muscle cells and fibroblasts. ECK is a type 1 transmembrane glycoprotein with an extracellular ligand-binding domain consisting of a cysteine-rich region followed by 3 fibronectin type 3 repeats. The intracellular domain of ECK has a tyrosine kinase catalytic domain that initiates a signal transduction cascade that reflects ECK function. ECK binds and is then activated by its counter-receptor, ligand for eff-associated kinase (LERK) -1, which can be readily induced in lineage-limiting ways with pre-inflammatory cytokines such as IL-1 or TNF. Is an immediate early response gene product. Soluble LERK-1 has been shown to partially promote angiogenesis by stimulating ECK in a mouse model of corneal angiogenesis. Unlike their normal controls, tumor cells of various lineages structurally express LERK-1 and this expression can be further upregulated by hypoxia and pre-inflammatory cytokines. Many such tumor cells also express ECK at higher levels than their normal controls, creating an opportunity for autoclean stimulation via ECK: LERK-1 interaction. Increased expression of both ECK and LERK-1 correlates with the transformation of melanoma from noninvasive lateral growth to highly invasive vertical growth metastatic melanoma. ECK: LERK-1 interaction is thought to promote tumor growth through its tumor growth promoting and angiogenic effects. Thus, inhibition of ECK tyrosine kinase activity mediated signaling cascades induced by binding and crosslinking of ECK with LERK-1 can be therapeutically beneficial in cancer, inflammatory diseases and hyperproliferative disorders. As described below, the compounds of the present invention inhibit the tyrosine kinase activity of ECK and are therefore useful for the treatment of the aforementioned disorders.

Growth of most solid tumors depends on angiogenesis, including activation, proliferation and subsequent differentiation of vascular endothelial cells into the dermis and capillaries. Angiogenesis of tumors makes them accessible to blood-originated oxygen and nutrients, and also provides them with adequate perfusion. Therefore, angiogenesis inhibition is an important therapeutic strategy in cancer and many chronic diseases such as rheumatoid arthritis, psoriasis, diabetic retinopathy, age-related spot degeneration and the like. Tumor cells produce a number of angiogenic molecules. Vascular endothelial growth factor (VEGF) is one such angiogenesis factor. Homodimeric disulfide-binding members of the VEGF, PDGF family are endothelial cell-specific mitotic substances and are known to reliably increase vascular endothelial permeability in affected tissues. VEGF is also an anti-aging survival factor of endothelial cells. Almost all nucleated tissues in the body have the ability to express VEGF in response to various stimuli, including hypoxia, sugar deficiency, progressive glycation products, inflammatory cytokines, and the like. The growth-promoting angiogenic effect of VEGF is primarily mediated through its signaling receptor kinase insertion domain containing receptor (KDR). Although expression of KDR is poor on most endothelial cells, activation with angiogenesis results in significant upregulation of KDR on endothelial cells. Most angiogenic vessels express high levels of KDR. KDR is a receptor protein tyrosine kinase with a cytoplasmic domain containing an extracellular VEGF-binding domain consisting of 7 immunoglobulin-like domains and a catalytic tyrosine kinase domain partitioned by a kinase-insertion region. Binding to VEGF results in dimerization of KDR resulting in its automatic phosphorylation and initiation of a signaling cascade. Tyrosine kinase activity of KDR is essential for mediating its functional effects as receptors for VEGF. Inhibition of KDR-mediated functional effects by inhibiting the catalytic activity of KDR is believed to be an important therapeutic strategy in the treatment of angiogenic disease symptoms, including cancer. As described below, the compounds of the present invention inhibit the tyrosine kinase activity of KDR and are therefore useful for the treatment of the aforementioned disease symptoms.

In addition to the above uses, some compounds of the present invention are useful for the preparation of other compounds of the present invention.

Compounds of the invention are certain substituted 3-cyano quinolines. Throughout this patent application, the quinoline ring system will be numbered as mentioned in the following formula: The numbering of the quinazoline ring system is also shown:

3-cyano quinoline has not been reported to have biological activity as an inhibitor of protein tyrosine kinase. 3-cyano quinoline with 4- (2-methylanilino) substituents having high concentrations of gastric (H ⁺ / K ⁺ ) -ATPase inhibitory activity has been described [Ife RJ, et al., J. Med. Chem., 35 (18), 3413 (1992).

Unlike compounds of the present invention, quinoline without a 3-cyano substituent is unsubstituted at the 4-position but reported as an inhibitor of protein tyrosine kinase [Gazit A., et al., J, Med. Chem., 39 (11), 2170 (1996)]. A series of quinolines with 3-pyridyl substituents and no 4-position substituents have been described as inhibitors of platelet induced growth factor receptor kinase [Dolle R. E., et al., J. Med. Chem., 372, 2627 (1994) and Maguire M, P., et al., J. Med. Chem., 372, 129 (1994). Patent applications WO 96/09294 and WO-9813350 describe inhibitors of protein tyrosine kinases comprising 4-anilinoquinoline which have various substituents at positions 5-8 but must also have hydrogen or fluorine atoms at position 3 . US Pat. No. 5,480,883 describes quinoline derivatives that are inhibitors of protein tyrosine kinases, but these derivatives do not have a specific combination of substituents, including 3-cyano groups, contained in the compounds of the invention. Applications WO-9802434 and WO-9802438 describe quinoline derivatives that are tyrosine kinase inhibitors, but these quinolines do not have important 3-cyano substituents.

In addition to quinoline, certain quinazoline derivatives that are similar in some respects to the compounds of the present invention are known as inhibitors of protein tyrosine kinases. Application EP-520722 describes 4-anilinoquinazoline containing simple substituents such as chloro, trifluoromethyl or nitro groups in the 5-8 positions. Application EP-566226 is a similar but much more diverse substituent that is allowed in positions 5 to 8 in the present invention. Application WO-9609294 describes compounds having similar substituents at positions 5 to 8 and substituents consisting of some polycyclic ring systems at position 4. Some simple substituted quinazolines are also described in applications WO-9524190, WO-9521613 and WO-9515758. Applications EP-602851 and WO-9523141 include similar quinazoline derivatives in which the aryl groups bonded at the 4 position may be of various heterocyclic ring structures. Application EP-635498 describes certain quinazoline derivatives having alkenoylamino and alkinoylamino groups among the substituents at position 6 and halogen atoms at position 7. Application WO-9519774 is a compound in which one or more carbon atoms in positions 5-8 can be replaced with heteroatoms resulting in various acyclic systems and are left- and 5-membered and 6-membered heterocyclic rings, and also various substituents are allowed on the left ring It explains. Application EP-682027-A1 describes certain pyrrolopyrimidine inhibitors of PTK. Application WO-9519970 describes compounds wherein the inhibitors resulting from the replacement of aromatic left rings of basic quinazoline structures with various different heterocyclic rings are tricyclic. Application EP-635507 describes quinazolines in which an additional 5- or 6-membered heterocyclic ring in which any substitution has occurred is fused at the 5 and 6 positions.

In addition to the aforementioned patent applications, a number of publications describe 4-anilinoquinazoline: Fry, D. W., et. al., Science, 265, 1093 (1994), Rewcastle G. W., et. al., J. Med. Chem., 38, 3482 (1995) and Bridges, A. J., et. al., J. Med. Chem., 39, 267, (1996). There is no publication describing 3-cyano quinoline as a PTK inhibitor.

The present invention relates to certain substituted 3-cyano quinoline compounds and pharmaceutically acceptable salts thereof. Compounds of the invention inhibit abnormal growth of certain cell types by inhibiting the action of certain growth factor receptor protein tyrosine kinases (PTKs) and other protein kinases. Therefore, the compounds of the present invention are useful for the treatment of certain diseases that are the result of unregulated PTK. The compounds of the present invention are anticancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of the present invention are useful for the treatment of cystic fossils in mammals. The present invention also relates to a process for the preparation of 3-cyano quinoline, its use for the treatment of cancer and cysticosins and pharmaceutical preparations containing the same.

The present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof:

In the above formula,

X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, and the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O and S, provided that acyclic hetero Aryl rings do not contain OO, SS, or SO bonds, and acyclic aryl or bicyclic heteroaryl rings are halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, 2 Alkynyl of 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1- Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, Phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkenes of 1-6 carbon atoms Amino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkino of 3-8 carbon atoms Monoamino, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, 3-10 From the group consisting of N, N-dialkylaminoalkyl of carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino Substituents selected may optionally be mono-, di-, tri- or tetra-substituted;

X is a chemical formula Radicals wherein A is a pyridinyl, pyrimidinyl or phenyl ring; the pyridinyl, pyrimidinyl or phenyl ring is halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, Alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1 Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, of 2-7 carbon atoms Carboalkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, 1-6 Alkanoylamino of carbon atom, Alkenoylamino of 3-8 carbon atom, Alkynoylamino of 3-8 carbon atom, 2-7 shots Carboxyalkyl of atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N- of 3-10 carbon atoms Optionally mono- with a substituent selected from the group consisting of dialkylaminoalkyl, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino Or di-substituted; T is bonded to carbon of A, which is -NH (CH ₂ ) _m- , -O (CH ₂ ) _m- , -S (CH ₂ ) _m- , -NR (CH ₂ ) _m -,-(CH ₂ ) _m -,-(CH ₂ ) _m NH-,-(CH ₂ ) _m O-,-(CH ₂ ) _m S- or-(CH ₂ ) _m NR-; Unsubstituted phenyl ring or halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, Halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1-6 carbon atoms Alkoxy, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, Phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2-12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms , Alkenoylamino of 3-8 carbon atoms, alkinoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, 1-5 carbon Aminoalkyl of atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, 3-10 Mono-, di- or t-substituted substituents selected from the group consisting of N, N-dialkylaminoalkoxy, mercapto and benzoylamino of a carbon atom - a ring-substituted phenyl; Provided that L can be an unsubstituted phenyl ring only when m> 0 and T is not -CH ₂ NH- or -CH ₂ O-; L is a 5 or 6 membered heteroaryl ring wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O and S, provided that the heteroaryl ring contains no OO, SS or SO bonds and the heteroaryl ring is halogen , Oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl Alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, trifluoromethyl of 1-6 carbon atoms, Cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, of 1-6 carbon atoms Alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkano of 1-6 carbon atoms Amino, alkenoylamino of 3-8 carbon atoms, alkinoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, 1-5 Aminoalkyl of carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, 3- Optionally mono- or di-substituted with a substituent selected from the group consisting of 10 carbon atoms of N, N-dialkylaminoalkoxy, mercapto and benzoylamino;

Z is -NH-, -O-, -S- or -NR-;

R is alkyl of 1-6 carbon atoms or carboalkyl of 2-7 carbon atoms;

G ₁ , G ₂ , R ₁ and R ₄ are each independently hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, 2- Alkenyloxy of 6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, 3 Alkynyloxy of 8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynyloxymethyl of 4-9 carbon atoms, 2- Alkoxymethyl of 7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, 1 Alkylsulfonamido of 6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, Cyano, Tro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxy of 1-4 carbon atoms Amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N of 4 to 12 carbon atoms Alkenylamino, N, N-dialkenylamino, phenylamino, benzylamino of 6-12 carbon atoms,

Or R ₁ and R ₄ are as described above and G ₁ or G ₂ or both R ₂ -NH-; If the substituents R ₁ , G ₂ , G ₃ or R ₄ are located on adjacent carbon atoms they can be taken together as a _divalent radical -OC (R ₆ ) ₂ -O-;

Y is Divalent radicals selected from the group consisting of;

R ₇ is —NR ₆ R ₆ , —OR ₆ , —J, —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR) ₆ ;

M is> NR ₆ , -O-,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p -OR ₆ ;

W is> NR ₆ , -O- or a bond;

Het is morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S, S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran and Het is optionally mono- or di-substituted with R ₆ on carbon or nitrogen and optionally mono- or di-substituted with hydroxy, -N (R ₆ ) ₂ or -OR ₆ on carbon; Optionally mono- or di-substituted with a monovalent radical-(C (R ₆ ) ₂ ) _s OR ₆ or-(C (R ₆ ) ₂ ) _s N (R ₆ ) ₂ on carbon and divalent on saturated carbon Optionally substituted with a radical —O— or —O (C (R ₆ ) ₂ ) _s O—;

R ₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, 2-7 carbon atoms Carboalkyl, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms , Dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1-6 carbons Alkylthio, hydroxy, carboxyl of atoms, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms Or alkyl of 1-6 carbon atoms, provided that the alkenyl or alkynyl moiety is combined with a nitrogen or oxygen atom via a saturated carbon atom. To sum up;

R ₂ is

It is selected from the group consisting of;

R ₃ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,

Is;

R ₅ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,

Is,

R ₈ and R ₉ are each independently — (C (R ₆ ) ₂ ) _r NR ₆ R ₆ or — (C (R ₆ ) ₂ ) _r OR ₆ ;

J is independently hydrogen, chlorine, fluorine or bromine;

Q is alkyl or hydrogen of 1-6 carbon atoms;

a = 0 or 1;

g = 1-6;

k = 0-4;

n is 0-1;

m is 0-3;

p = 2-4;

q = 0-4;

r = 1-4;

s = 1-6;

u = 0-4 and v = 0-4 and the sum of u + v is 2-4;

Provided that if R ₆ is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, these alkenyl or alkynyl moieties are bonded to nitrogen or oxygen atoms via saturated carbon atoms;

When Y is -NR ₆ -and R ₇ is -NR ₆ R ₆ , -N (R ₆ ) ₃ ⁺ or -NR ₆ (OR ₆ ), g = 2-6;

When M is -O- and R ₇ is -OR _6, p = 1-4;

If Y is —NR ₆ — then k = 2-4;

When Y is -O- and M or W is -O-, k = 1-4;

Q = 2-4 unless W is a bond to Het bonded via a nitrogen atom;

If W is a bond to Het bonded through a nitrogen atom and Y is -O- or -NR ₆ -then k = 2-4.

Pharmaceutically acceptable salts include: acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, malonic acid, gluconic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, and similar known acceptable acids. And those derived from the same organic and inorganic acids.

Preferred bicyclic aryl or bicyclic heteroaryl ring systems include naphthalene, 1,2,3,4-tetrahydronaphthalene, indane, 1-oxo-indane, 1,2,3,4-tetrahydroquinoline, naphthyridine , Benzofuran, 3-oxo-1,3-dihydro-isobenzofuran, benzothiaphene, 1,1-dioxo-benzothiaphene, indole, 2,3-dihydroindole, 1,3-dioxo -2,3-dihydro-1H-isoindole, benzotriazole, 1H-indazole, indolin, benzopyrazole, 1,3-benzodioxol, benzoxazole, purine, phthalimide, coumarin, cros Mon, quinoline, terahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido [2,3-b] pyridine, pyrido [3,4-b] pyrazine, pyrido [3,2-c] pyridine Chopped, pyrido [3,4-b] pyridine, 1H-pyrazole [3,4-d] pyrimidine, 1,4-benzodioxane, putridine, 2 (1H) -quinolone, 1 (2H) Isoquinolone, 2-oxo-2,3-dihydro-benzthiazole, 1,2-methylenedioxybenzene, 2-oxindol, 1,4-benzisox, Jothiazol, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoazine, phthalazine, 1,4-dioxo-1, 2,3,4-tetrahydro-phthalazine, 2-oxo-1,2-dihydro-quinoline, 2,4-dioxo-1,4-dihydro-2H-benzo [d] [1,3 ] Oxazine, 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [e] [1,4] diazepine or cynoline.

If L is a 5- or 6-membered heteroaryl ring, preferred heteroaryl rings are pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole or 1,2,4-triazole. Include.

One or both of the rings of the bicyclic aryl or bicyclic heteroaryl group can be fully unsaturated, partially saturated or fully saturated. Oxo substituents on bicyclic aryl or bicyclic heteroaryl residues mean that one of the carbon atoms has a carbonyl group. Thio substituents on acyclic aryl or bicyclic heteroaryl residues mean that one of the carbon atoms has a thiocarbonyl group.

If L is a 5 or 6 membered heteroaryl ring, it may be fully unsaturated, partially saturated or fully saturated. Heteroaryl rings may be bonded to A via carbon or nitrogen. Oxo substituents on heteroaryl rings mean that one of the carbon atoms has a carbonyl group. Thio substituent on a heteroaryl ring means that one of the carbon atoms has a thiocarbonyl group.

Alkyl, alkoxy, alkanoyloxy, alkoxymethyl, alkanoyloxymethyl, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, carboalkoxy, carboalkyl, carboxyalkyl, carboalkoxyalkyl, alkanoylamino, N-alkylcarba The alkyl and alkyl moieties of N, N-dialkylcarbamoyl, N-alkylaminoalkoxy, N, N-dialkylaminoalkoxy include both straight and branched carbons. Alkenyl moieties of alkenyl, alkenoyloxymethyl, alkenyloxy, alkenylsulfonamido substituents include both straight and branched carbon and one or more unsaturated regions and all possible configurational isomers. Alkynyl, alkynyloxymethyl, alkynylsulfonamido, alkynyl moieties of alkynyloxy substituents include both straight and branched carbon and one or more unsaturated regions. Carboxy is defined as -CO ₂ H radical. Carboalkoxy of 2-7 carbon atoms is defined as the —CO ₂ R ″ radical, where R ″ is an alkyl radical of 1-6 carbon atoms. Carboxyalkyl is Defined as a radical, where Is a divalent alkyl radical of 1-6 carbon atoms. Carboalkoxyalkyl Defined as a radical, where Is a divalent alkyl radical and R " and Together have 2-7 carbon atoms. Carboalkyl is defined as a -COR "radical, where R" is an alkyl radical of 1-6 carbon atoms. Alkanoyloxy is defined as the -OCOR "radical, where R" is an alkyl radical of 1-6 carbon atoms. Alkanoyloxymethyl is defined as an R ″ CO ₂ CH ₂ -radical, where R ″ is an alkyl radical of 1-6 carbon atoms. Alkoxymethyl is defined as an R "OCH ₂ -radical, where R" is an alkyl radical of 1-6 carbon atoms. Alkylsulfinyl is defined as an R "SO- radical, where R" is an alkyl radical of 1-6 carbon atoms. Alkylsulfonyl is defined as an R ″ SO ₂ -radical, where R ″ is an alkyl radical of 1-6 carbon atoms. Alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamido are defined as R "SO ₂ NH- radicals, where R" is each an alkyl radical of 1-6 carbon atoms, 2-6 carbon atoms Alkenyl radical or alkynyl radical of 2-6 carbon atoms. N-alkylcarbamoyl is defined as an R "NHCO- radical, where R" is an alkyl radical of 1-6 carbon atoms. N, N-dialkylcarbamoyl is defined as a R "R'NCO- radical, where R" is an alkyl radical of 1-6 carbon atoms, R 'is an alkyl radical of 1-6 carbon atoms, R ′ and R ″ may be the same or different. When X is substituted, it is preferred to be mono-, di- or tri-substituted, most preferably monosubstituted. At least one of substituents R ₁ and R ₄ is It is preferable that it is hydrogen, and most preferably both are hydrogen. It is also preferable that X is a phenyl ring, Z is -NH-, and n = 0.

Het may optionally be mono- or di-substituted with R ₆ on carbon or nitrogen, and optionally mono- or di-substituted on carbon with hydroxy, -N (R ₆ ) ₂ or -OR ₆ ,-( May optionally be mono- or di-substituted on carbon with C (R ₆ ) ₂ ) _s OR ₆ or-(C (R ₆ ) ₂ ) _s N (R ₆ ) ₂ , divalent -O- or -O ( C (R ₆ ) ₂ ) _s O- (carbonyl or canal group respectively) is a heterocycle as described above which may optionally be mono- or di-substituted on saturated carbon; In some cases where Het is substituted with —O— (carbonyl), the carbonyl group may be hydrated. Het may be bonded to W via a carbon atom on a heterocyclic ring if q = 0, or if Het is a heterocycle containing nitrogen and also containing a saturated carbon-nitrogen bond, such a heterocycle is nitrogen if W is a bond It can be combined with carbon through. If q = 0 and Het contains nitrogen and also contains an unsaturated carbon-nitrogen bond, the nitrogen atom of the heterocycle may bond with carbon if W is a bond and the resulting heterocycle will have a positive charge. If Het is substituted with R ₆ , this substitution may take place on the ring carbon, or in the case of heterocycles containing nitrogen and also containing saturated carbon-nitrogen, such nitrogen may be substituted with R ₆ , or containing nitrogen Also in the case of heterocycles containing unsaturated carbon-nitrogen, these nitrogens may be substituted with R ₆ and the heterocycle will carry a positive charge. Preferred heterocycles are pyridine, 2,6-disubstituted morpholine, 2,5-disubstituted thiomorpholine, 2-substituted imidazole, substituted thiazoles, N-substituted imidazoles, N-substituted 1,4-piperazines, N -Substituted piperadine and N-substituted pyrrolidine.

The compounds of the present invention may contain one or more asymmetric carbon atoms: in this case, the compounds of the present invention comprise diastereomers, racemates and their R and S enantiomers, respectively. Some compounds of the present invention may contain one or more double bonds; In such cases, the compounds of the present invention each comprise a possible configurational isomer and a mixture of these isomers.

Compounds having Formula 1 and salts thereof may be prepared by a process comprising the following steps:

(a) chemical formula Reacting a compound having R ₁ , G ₁ , G ₂ , R ₄ , Z, n and X as described above with a dehydrating agent to convert the aminocarbonyl group to a cyano group;

(b) a compound having formula A ₁ -NH-A ₂ or a salt thereof and a compound having formula QA ₃ , wherein Q is a leaving group and A ₁ , A ₂ and A ₃ are A ₁ -NA ₂ -A ₃ To a compound consistent with Formula 1);

(c) a compound having formula A ₄ -OH or a salt thereof, wherein the compound has formula QA ₅ , wherein Q is as defined above and A ₄ and A ₅ are compounds in which A ₄ -OA ₅ is consistent with formula 1; To react);

(d) An acid is added to the compound having Formula 1 to prepare an acid addition salt.

The preparation of compounds and intermediates of the invention according to formula 5 is illustrated in Scheme 1, wherein Z, X, n, R ₁ , G ₂ , G ₁ and R ₄ are as described above. In accordance with the series of reactions outlined in Scheme 1, the quinoline-3-carboxylic acid ester of formula 2 is hydrolyzed to a base to provide the carboxylic acid of formula 3. The carboxylic acid group of formula (3) is converted to acyl imidazole by heating it with carbonyldiimidazole in an inert solvent such as dimethylformamide (DMF) to give amide (4) by addition of ammonia. Dehydration of the amide functional groups with dehydrating agents such as trifluoroacetic anhydride in pyridine, phosphorus pentoxide in an inert solvent and the like produces the 3-cyano quinoline (5) of the present invention. If the intermediates have asymmetric carbon atoms, they can be used as racemates or as R or S enantiomers, respectively, in which case the compounds of the invention will be in racemic or R and S optically active forms, respectively. The quinoline-3-carboxylic acid esters of formula (2), quinoline-3-carboxylic acids of formula (3) and quinoline-3-carboxylic amides of formula (4), which are necessary for preparing the compounds of the present invention, are already known in the art or are detailed in the following references. It may be prepared by procedures known in the art as described:

Sarges, Reinhard; Gallagher, Andrea; Chambers, Timothy J .; Yeh, Li An, J. Med. Chem, 36, 2828 (1993); Savini, Luisa; Massarelli, Paola; Pellerano, Cesare; Bruni, Giancarlo. Farmaco, 48 (6), 805 (1993); Ife, Robert J .; Brown, Thomas H .; Keeling, David J .; Leach, Colin, J. Med. Chem., 35, 3413 (1992); Hanifin, J. William; Capuzzi, Rosemary; Cohen, Elliott, J. Med. Chem., 12 (5), 1096 (1969); Marecki, Paul E .; Bambury, Ronald E., J. Pharm. Sci., 73 (8), 1141 (1984); Pellerano, C .; Savini, L .; Massarelli, P .; Bruni, G .; Fiaschi, A. I., Farmaco, 45 (3), 269, (1990); Marecki, Paul E .; Bambury, Ronald E., J. Pharm. Sci., 73 (8), 114 (1984); Patent application WO 8908105; US Patent 4343804; US Patent 3470186.

The preparation of compounds of the invention of formula 12 is illustrated in Scheme 2, wherein X, Z, n, R ₁ , G ₂ , G ₁ and R ₄ are as described above. Substituted aniline of formula (6) is heated with reagent (7) in the presence or absence of solvent to produce intermediate (8) in a mixture of isomers. Pyrolysis at 200-350 ° C. of (8) in a hot boiling solvent such as diphenyl ether produces 3-cyano quinolone of formula (9); These intermediates may also exist in the form of 4-hydroxyquinoline tautomers. When R ₄ is a hydrogen atom, the intermediate 9 may be formed as a mixture of two positional isomers. These isomers may be separated by methods well known in the art including fractional crystallization and chromatography, but are not limited thereto. The isolated isomers can then be converted individually to the compounds of the present invention. Alternatively, isomers may be separated later in the synthesis. Heating of compound (9) with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride in the presence or absence of solvent produces 4-chloro-3-cyano quinoline of formula (10). Condensation of (10) with the nucleophilic amine, aniline, mercaptan, thiophenol, phenol or alcohol reagent of formula 11 produces a 3-cyano quinoline intermediate of formula 12; This condensation can be promoted by heating the reaction mixture or by using a basic catalyst such as trialkylamine, sodium hydride in an inert solvent, sodium or potassium alkoxide in an alcohol solvent and the like. If the substituents can contribute to asymmetric carbon atoms, the intermediate can be used as racemate or as R or S enantiomer, respectively, in which case the compound of the invention will be in racemic or R and S photoactive form, respectively. . If a substituent can contribute to one or more asymmetric carbon atoms, diastereomers may be present; These may be separated by methods well known in the art including fractional crystallization and chromatography, but are not limited thereto. If the R ₁ , G ₂ , G ₁ and R ₄ residues contain primary or secondary amino groups, the amino groups may first need to be used in protected form prior to reaction with the reagent (7). Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The electron protecting group can be removed from the final product of formula 12 by treatment with an acid such as trifluoroacetic acid while the latter protecting group can be removed by catalytic hydrogenation. When the R ₁ , G ₂ , G ₁ and R ₄ residues contain hydroxyl groups, the hydroxyl groups may first need to be used in protected form prior to reaction with the reagent (7). Suitable protecting groups include, but are not limited to, t-butyldimethylsilyl, tetrahydropyranyl or benzyl protecting groups. The first two protecting groups can be removed from the final product of formula 12 by treatment with an acid such as acetic acid or hydrochloric acid while the latter protecting groups can be removed by catalytic hydrogenation.

The preparation of intermediate 15 (same as intermediate 9 in Scheme 2) can also be prepared as described in Scheme 3 below. Heating with dimethylformamide dimethyl acetal in the presence or absence of a solvent of the substituted aniline of Formula 13 produces an intermediate of Formula 14. The reaction in an inert solvent of the lithium anion of acetonitrile prepared using a base such as (14) and n-butyl lithium or the like can be converted to 3-cyano quinolone (15) or a compound of the present invention. Produces no-4-hydroxy quinoline tautomers. If the R ₁ , G ₂ , G ₁ and R ₄ residues contain primary or secondary amino groups, the amino groups may first need to be used in protected form. Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The electron protecting group can be removed from the final product of formula 15 by treatment with an acid such as trifluoroacetic acid while the latter protecting group can be removed by catalytic hydrogenation. When the R ₁ , G ₂ , G ₁ and R ₄ residues contain hydroxyl groups, the hydroxyl groups may first need to be used in protected form. Suitable protecting groups include, but are not limited to, t-butyldimethylsilyl, tetrahydropyranyl or benzyl protecting groups. The first two protecting groups can be removed from the final product of formula 15 by treatment with an acid such as acetic acid or hydrochloric acid while the latter protecting groups can be removed by catalytic hydrogenation.

The preparation of the compounds of the present invention of formula 24 is illustrated in Scheme 4, wherein R ₁ , G ₂ , R ₄ , Z, n and X have been defined. R ₁₀ is alkyl (preferably isobutyl) of 1-6 carbon atoms. R ₂ ′ is a radical selected from the group consisting of:

Wherein R ₆ , R ₃ , R ₅ , J, s, r, u and v have been defined.

According to the reaction outlined in Scheme 4, 4-chloro-3-cyano-6-nitroquinoline (16) is reacted with amine or aniline (17) by heating in an inert solvent such as tetrahydrofuran, butanol or methoxyethanol To produce a compound of formula 20 wherein Z is -NH-. The reaction of (16) with mercaptan or thiophenol (18) in an inert solvent can be carried out using a base such as sodium hydride to produce a compound of formula 20 wherein Z is -S-. The reaction of (16) with an inert solvent of alcohol or phenol (19) can be carried out using a base such as sodium hydride to produce a compound of formula 20 wherein Z is -O-. Compounds of formula 20 are either 6-amino by use of a reducing agent such as sodium hydrosulfite in a two-phase system consisting of tetrahydrofuran and water in the presence of a small amount of phase transfer catalyst or by the use of iron in a reflux protic solvent containing acetic acid or ammonium chloride. 3-cyano-quinoline (21) can be reduced. Acid chloride of formula 22 or mixed anhydride of formula 23 (corresponding carboxylic acid) in an inert solvent such as tetrahydrofuran (THF) in the presence of an organic base such as pyridine, triethylamine, diisopropylethylamine or N-methyl morpholine Acylation of (21) to the compounds of the present invention. If (22) or (23) has an asymmetric carbon atom, they can be used as racemates or as R or S enantiomers, respectively, in which case the compounds of the invention are racemates or R and S optically active, respectively It will be in the form. If R ₂ ′ contains a primary or secondary amino group, the amino group must first be protected prior to the formation of anhydride or acid chloride. Suitable protecting groups include, but are not limited to, tert-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ) protecting groups. The electron protecting group can be removed from the final product of formula 24 by treatment with an acid such as trifluoroacetic acid while the latter protecting group can be removed by catalytic hydrogenation. When R 2 ′ contains a hydroxyl group, the hydroxyl group may first need to be protected prior to the formation of anhydride or acid chloride. Suitable protecting groups include, but are not limited to, t-butyldimethylsilyl, tetrahydropyranyl or benzyl protecting groups. The first two protecting groups can be removed from the final product of formula 24 by treatment with an acid such as acetic acid or hydrochloric acid while the latter protecting groups can be removed by catalytic hydrogenation. If X in intermediates 17, 18 or 19 contains primary or secondary amino groups or hydroxyl groups, it may be necessary to protect these groups prior to reaction with (16). The same amine or alcohol protecting groups described above can be used and they can be removed from the product 24 as described above.

Using a method similar to that described above in Scheme 4, intermediate 25 may be converted to compound 26 of the present invention.

In order to prepare the compounds of the invention, certain amines are required. Some typical amines are shown in Listing A below, where R ₆ , p and r are as described above. These amines are commercially available and can be prepared by simple procedures known in the chemical literature or well known in the art. In some cases these amines may have asymmetric carbon atoms; They can be used as racemates or they can be dissolved and used as R or S enantiomers, respectively, in which case the compounds of the invention will be in racemic or respectively optically active forms. In the schemes shown below throughout this application, these amines and other similar amines will be represented by the general structure of formula (R ′) ₂ NH, where the formula may represent a primary or secondary amine. .

List A

Certain alcohols are needed to prepare the compounds of the present invention. Some typical alcohols are shown in Listing B below, where R ₆ , p and r are as described above. These alcohols are commercially available and can be prepared by simple procedures known in the chemical literature or well known in the art. In some cases these alcohols may have asymmetric carbon atoms; They may be used as racemates or they may be dissolved and used as R or S enantiomers, respectively, in which case the compounds of the invention will be in racemic or respectively optically active form. In the schemes described below throughout this application, these alcohols and other similar alcohols will be represented by the general structure of the formula R'OH.

List B

Certain mixed anhydrides of Formulas 31, 34, and 38 are needed to prepare some of the compounds of the present invention; They are prepared as outlined in Scheme 5-6, wherein R ₆ , R ₁₀ , X, Z, n and s are as described above. J 'is a halogen atom chlorine, bromine or iodine or a tosleyate (p-toluenesulfonate) or mesylate (methanesulfonate) group. The reaction of (27) with the amines of list A is achieved by heating in an inert solvent such as tetrahydrofuran or N, N-dimethylformamide or by using potassium or cesium carbonate in acetone. The temperature and time of heating will depend on the reactivity of (27); If s is 1 or more, a long time reaction and high temperature may be required. Treatment with (28) with an alkyl lithium reagent followed by cooling to a dry carbon dioxide atmosphere provides the carboxylic acid of formula 29. They can be converted to mixed anhydrides of Formula 31 using reagents such as isobutylchloroformate in an inert solvent such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of the present invention as described above in Scheme 4. The reaction of (27) with the alcohols of list B is achieved using sodium hydride or other non-nucleophilic bases such as potassium or cesium carbonate in an inert solvent such as tetrahydrofuran, acetone or N, N-dimethylformamide . In some cases, the alcohols of List B may also be solvents of the reaction. Treatment with (32) with an alkyl lithium reagent followed by cooling to a dry carbon dioxide atmosphere provides the carboxylic acid of formula 33. These can be converted to mixed anhydrides of formula 34 using reagents such as isobutylchloroformate in an inert solvent such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides can then be used to prepare the compounds of the present invention as described above in Scheme 4.

As R ₁ , G ₂ , R ₄ , R ₆ , R ₁₀ , X, Z, n and s are outlined in Scheme 6 as described above, alcohol 35 is triethylamine and 4-N, N- In the presence of dimethylamino pyridine (DMAP), each can be protected with a t-butyl dimethylsilyl protecting group by reaction with silyl chloride in methylene chloride. The resulting protected alcohol 36 is converted to an acetylene-based Grignard reagent, which is then maintained under a dry carbon dioxide atmosphere to produce carboxylic acid 37. As mentioned above they are converted to mixed anhydride 38 and reacted with 6-amino-3-cyanoquinoline 39 to produce (40). In the final step of the process, the silyl protecting group is removed by treatment with an acid in a protic solvent mixture to produce the compound represented by formula (41).

The compounds of the present invention are also prepared as described in Scheme 7, wherein R ₁ , G ₂ , R ₄ , R ₆ , R ₁₀ , X, Z, n and s are as described above. J 'is a halogen atom chlorine, bromine or iodine, or a tosleyate or mesylate group. Treatment at low temperature with alkyl lithium reagent of (42) followed by cooling with a dry carbon dioxide atmosphere provides the carboxylic acid of formula 43. These can be converted to mixed anhydrides of formula 44 using reagents such as isobutylchloroformate in an inert solvent such as tetrahydrofuran in the presence of a base such as N-methylmorpholine. These anhydrides may then be used to prepare the compounds of the present invention by reaction with 6-amino-3-cyanoquinoline 45 as described above in the scheme. The reaction with the alcohols of list B of (46) is carried out using sodium hydride or other non-nucleophilic base in an inert solvent such as tetrahydrofuran or N, N-dimethylformamide, represented by (47). Produce the compound of the invention. In some cases, the alcohols of List B may also be solvents of the reaction. The reaction of (46) with the amines of list A to produce the compounds of the invention represented by (48) is carried out by heating in an inert solvent such as tetrahydrofuran or N, N-dimethylformamide or potassium or cesium in acetone. This is accomplished by using carbonates. The temperature and time of heating will depend on the reactivity of (46); If s is 1 or more, a long time reaction and high temperature may be required.

Using a method similar to that summarized above, 45b can be converted to 47b or 48b.

Other carboxylic acid chlorides and anhydrides necessary to prepare some of the compounds of the present invention are prepared as described in Scheme 8, wherein R ₆ , R ₃ , R ₁₀ , X, Z, J ', n and s are described above. As shown. Q 'is an alkyl group of 1-6 carbon atoms. Esters 49, 53 or 57 are hydrolyzed to bases such as barium hydroxide to produce carboxylic acids 50, 54 or 58, respectively. These acids are mixed either by oxalyl chloride and catalyst N, N-dimethylformamide in an inert solvent, respectively, by carboxylic acid chloride (51 or 56) or by using organic bases such as isobutyl chloroformate and N-methylmorpholine, respectively. It can be converted to anhydride 55 or 59. Leaving groups in the compound represented by Formula 52 may be replaced by the amines of list A or alcohols of list B using the procedures described above to produce intermediates 57 and 53, respectively. These carboxylic acid chlorides 51 and 56 and these anhydrides 55 and 59 can be used to prepare some compounds of the present invention by using the methods outlined in the above schemes herein.

By using the same method as outlined in Scheme 8 above, it is also possible to prepare analogous carboxylic acid chlorides and anhydrides given in Listing C below, wherein R ₆ , R ₃ , p and s are as described above. G is radical:

ego:

A is a radical -N (R ') ₂ , -OR' or -J '(wherein -N (R') ₂ is derived from an amine of list A, -OR 'is derived from an alcohol of list B , J 'is a leaving group as described above).

By using these carboxylic acid chlorides and anhydrides and then using the methods outlined in the above schemes and carrying out the details set forth in the examples presented below, a number of compounds of the invention can be prepared.

List C

Compounds of the present invention represented by Formula 62-63 may be prepared as described in Scheme 9, wherein R ₁ , G ₂ , R ₄ , R ₆ , R ₃ , R ₁₀ , X, Z, J ', n and s are as described above. The reaction of 6-amino-3-cyanoquinoline (61) with carboxylic acid chloride (60) using an organic base in an inert solvent produces a compound of the present invention represented by formula (62). The reaction of (62) with the alcohols of list B is carried out using sodium hydride or other non-nucleophilic bases such as potassium or cesium carbonate in an inert solvent such as tetrahydrofuran, acetone or N, N-dimethylformamide The compound of this invention represented by (63) is produced. In some cases, the alcohols of List B may also be solvents of the reaction. The reaction of (62) with the amine of list A to obtain the compound of the present invention represented by (64) is accomplished by heating in an inert solvent such as tetrahydrofuran or N, N-dimethylformamide. The heating temperature and time will depend on the reactivity of (62): If s is 1 or more, prolonged reaction and high temperature may be required. In addition, by using this method, the carboxylic acid chlorides and mixed anhydrides listed in Listing C can be used to prepare analogous compounds of the invention.

By applying the method outlined above, 61b can be converted to 63b and 64b via intermediate 62b.

The reaction of the heterocycle HET containing (62) or (62b) with nitrogen and also containing unsaturated carbon-nitrogen bonds is achieved by refluxing in an inert solvent and the compounds of the invention (64c and 64d), respectively, in which the compound is positively charged To produce. The counter anion J'- may be replaced with another pharmaceutically acceptable anion using a suitable ion exchange resin.

Some compounds of the present invention can be prepared as outlined in Scheme 10, wherein R ₁ , G ₂ , R ₃ , R ₄ , R ₆ , R ₁₀ , X, Z, J ', n and r are described above Same as one. Acetylene-based alcohol 65 may be coupled with halide, mesylate or tosylate 66 using a base such as sodium hydride in an inert solvent such as tetrahydrofuran. The resulting acetylene 67 is then treated with an alkyl lithium reagent at low temperature. Maintaining the reaction under a carbon dioxide atmosphere then produces carboxylic acid 68. They are then reacted with 6-amino-3-cyanoquinoline (69) through mixed anhydrides to produce the compounds of the present invention represented by formula (70). Alternatively, intermediate 67 may be prepared by starting with alcohol 71 and first treating it with a base such as sodium hydride in an inert solvent such as tetrahydrofuran and then adding acetylene 72 with the appropriate leaving group. have. In a similar manner, amino alcohols represented by the formula (R ₆ ) ₂ N- (C (R ₆ ) ₂ ) _r -OH by reacting with (72) and applying the chemistry of Scheme 10 are of the present invention Can be converted to a compound:

By applying the same method as described above, (69b) can be converted into the compound of the present invention represented by (70b).

Compounds of the present invention represented by Formulas 76 and 77 are prepared as described in Scheme 11, wherein R ₁ , R ₃ , R ₄ , R ₆ and n are as described above and amine HN (R ″) ₂ is It is selected from the following group:

Refluxing (73) and (74) in a solvent such as ethanol yields an intermediate (75) which can react with an amine in reflux ethanol to produce the compound of formula (76). Treatment of (75) with an excess of sodium alkoxide in an inert solvent or a solvent in which an alkoxide is induced yields a compound of the invention of formula 77.

In the same manner as described above, 74b can be converted to 76b or 77b.

Compounds of the present invention represented by Formula 83 can be prepared as described in Scheme 12, wherein R ₁ , G ₂ , R ₄ , R ₆ , R ₃ , R ₁₀ , X, Z, n and r are described above Same as one. The reaction of the mercapto carboxylic acid 78 with the reagent 79 produces a compound represented by the formula (80). Alternatively, (80) can be prepared from mercaptan R ₃ SH using mercapto acid (78), triethylamine and 2,2'-dipyridyl disulfide. Condensation with 6-amino-3-cyanoquinoline 82 followed by formation of mixed anhydride to yield (81) yields the compounds of the present invention.

By applying a method similar to the above, 82b can be converted to 83b.

Compounds of the present invention represented by Formula 86-88 can be prepared as described in Scheme 13, wherein R ₁ , G ₂ , R ₁ , R ₄ , R ₅ , J ', X, Z and n are described above Same as one. Q 'is alkyl of 1-6 hydrogen atoms, alkoxy, hydroxy or hydrogen of 1-6 hydrogen atoms. Alkylation of (84) to 6-amino-3-cyanoquinoline (85) was carried out by heating with a base such as potassium carbonate in an inert solvent such as N, N-dimethylformamide to form The compounds of the invention can be produced. If Q 'is alkoxy, the ester group can be hydrolyzed to the acid using a base such as sodium hydroxide in methanol. In a similar manner, by using the intermediates 89 and 90, the compounds of the present invention represented by the formulas 87 and 88 can be prepared, respectively.

By applying a method similar to the above, 85b can be converted to 86b-88b.

Compounds of the present invention represented by Formula 93 may be prepared as described in Scheme 14, wherein R ₁ , G ₂ , R ₁ , R ₄ , R ₅ , X, Z and n are as described above. The reaction of reagent 91 with 6-amino-3-cyanoquinoline 92 is carried out using an organic base excess such as triethylamine and an inert solvent such as tetrahydrofuran to represent the compound of formula 93 To produce.

Compounds of the present invention represented by Formula 96 may be prepared by Mitsunobu reaction of phenol (94) with alcohol (95) in an inert solvent, as described in Scheme 15, wherein R ₁ , G ₁ , R ₁ , R ₄ , R ₅ , R ₆ , W, Het, X, Z, k and n are as described above. Alternatively, the Mitsunobu reaction can be applied to compound (97) to produce (98). This compound can be converted to (96) as described above in Scheme 4. The heterocycle can be introduced at the 6-position by using the corresponding compound, wherein G ₁ is hydroxy and G ₂ is located at the 7-position.

There are certain functional group manipulations useful for preparing the compounds of the invention that can be applied to the various intermediates 3-cyanoquinoline and the final compounds of the invention. These manipulations mean substituents R ₁ , G ₁ , G ₂ or R ₄ located in the 3-cyanoquinoline shown in the above scheme. Some of these functional group manipulations are described below:

If at least one of R ₁ , G ₁ , G ₂ or R ₄ is a nitro group it can be converted into the corresponding amino group by reduction with acetic acid or by catalytic hydrogenation in acetic acid. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is an amino group, this is by heating in an inert solvent to alkylation of at least 2 equivalents of alkyl halides of 1 to 6 carbon atoms or of 1 to 6 carbon atoms It may be converted to the corresponding dialkylamino group of 2 to 12 carbon atoms by reduction alkylation using a reducing agent such as aldehyde and sodium cyanoborohydride. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is a methoxy group, it is heated with pyridinium chloride in the inert solvent by reaction with a demethylating agent such as boron tribromide or in the presence or absence of a solvent. Thereby converting to the corresponding hydroxy group. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is an amino group, it is an alkylsulfonyl chloride, alkenylsulfonyl chloride or alkynylsulfonyl, respectively, in an inert solvent using a basic catalyst such as triethylamine or pyridine Reaction with chlorides can be converted to the corresponding alkylsulfonamido, alkenylsulfonamido or alkynylsulfonamido groups of 2 to 6 carbon atoms. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is an amino group, it is by alkylation of 1 to 6 carbon atoms to 1 equivalent of alkyl halide by heating in an inert solvent or by water or alcohol or their In a protic solvent such as a mixture, it can be converted to the corresponding alkyl amino group of 1 to 6 carbon atoms by reduction alkylation using a reducing agent such as aldehyde of 1 to 6 carbon atoms and sodium cyanoborohydride. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is hydroxy, it is the corresponding 1- by reaction with a suitable carboxylic acid chloride, anhydride or mixed anhydride in an inert solvent using pyridine or trialkylamine as catalyst. It can be converted to an alkanoyloxy group of six carbon atoms. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is hydroxy, it is 1-6 by reaction with a suitable carboxylic acid chloride, anhydride or mixed anhydride in an inert solvent using pyridine or trialkylamine as catalyst Can be converted to the corresponding alkenoyloxy group of the carbon atom. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is hydroxy, it is reacted with the appropriate carboxylic acid chloride, anhydride or mixed anhydride in an inert solvent using pyridine or trialkylamine as catalyst. It can be converted to an alkinoyloxy group of four carbon atoms. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is a carboxy or carboalkoxy group of 2-7 carbon atoms, it is a suitable reducing agent such as borane, lithium borohydride or lithium aluminum hydride in an inert solvent. By reduction to a corresponding hydroxymethyl group; The hydroxymethyl group is then converted to the corresponding halomethyl group by reaction with a halogenating agent such as phosphorus tribromide or phosphorus pentachloride to produce the bromomethyl group in an inert solvent. Can be. The hydroxymethyl group is acylated with a suitable acid chloride, anhydride or mixed anhydride in an inert solvent using pyridine or trialkylamine as catalyst, corresponding alkanoyloxymethyl group of 2-7 carbon atoms, 2-7 carbons It is possible to produce compounds of the invention having alkenoyloxymethyl groups of atoms or alkinoyloxymethyl groups of 2-7 carbon atoms. If at least one of R ₁ , G ₁ , G ₂ or R ₄ is a halomethyl group, it can be converted to an alkoxymethyl group of 2-7 carbon atoms by replacing the halogen atom with sodium alkoxide in an inert solvent. If at least one of R ₁ , G ₁ , G _2, or R ₄ is a halomethyl group, it is substituted with an aminomethyl group, 2-7 carbon atoms, by replacing the halogen atoms with ammonia, primary or secondary amines, respectively, in an inert solvent. N-alkylaminomethyl groups or N, N-dialkylaminomethyl groups of 3-14 carbon atoms.

In addition to the methods described above herein, there are a number of patent applications that describe methods useful for the preparation of the compounds of the present invention. Although these methods describe the preparation of certain quinazolines, they are also applicable to the preparation of the corresponding substituted 3-cyanoquinolines. The chemical procedure described in application WO-9633981 can be used to prepare 3-cyanoquinoline intermediates for use in the present invention, wherein R ₁ , G ₁ , G ₂ or R ₄ are alkoxyalkylamino groups. The chemical procedure described in application WO-9633980 can be used to prepare 3-cyanoquinoline intermediates for use in the present invention, wherein R ₁ , G ₁ , G ₂ or R ₄ are aminoalkylalkoxy groups. The chemical procedure described in application WO-9633979 can be used to prepare 3-cyanoquinoline intermediates for use in the present invention, wherein R ₁ , G ₁ , G ₂ or R ₄ are alkoxyalkylamino groups. The chemical procedure described in application WO-9633978 can be used to prepare 3-cyanoquinoline intermediates for use in the present invention, wherein R ₁ , G ₁ , G ₂ or R ₄ are aminoalkylamino groups. The chemical procedure described in application WO-9633977 can be used to prepare 3-cyanoquinoline intermediates for use in the present invention, wherein R ₁ , G ₁ , G ₂ or R ₄ are aminoalkylalkoxy groups. Although the patent application describes compounds in which the functional groups mentioned are introduced at the 6-position of quinazoline, the same chemical is identical to the position occupied by the R ₁ , G ₁ , G ₂ and R ₄ substituents of the compounds of the invention Can be used to introduce groups.

Typical compounds of the present invention are evaluated by a number of standard pharmaceutical test procedures showing that the compounds of the present invention are antiproliferative agents with significant activity as inhibitors of protein tyrosine kinases. Based on the activity shown by standard pharmaceutical test procedures, the compounds of the present invention are useful as antineoplastic agents. The test procedure used and the results collected are described below.

Inhibition of Epidermal Growth Factor Receptor Kinase (EGF-R) Using Recombinant Enzymes

Typical test compounds are evaluated for their ability to inhibit the phosphorylation of tyrosine residues of peptide substrates catalyzed by the enzyme epidermal growth factor receptor kinase. The peptide substrate (RR-SRC) has the sequence arg-arg-leu-ile-glu-asp-ala-glu-tyr-ala-ala-arg-gly. The enzyme used in this test is the His-tag cytoplasmic domain of EGFR. Recombinant baculovirus (vHcEGFR52) containing Met-Ala- (His) ₆ followed by EGFR cDNA encoding amino acids 645-1186 is constructed. Sf9 cells in a 100 mm plate were infected with a multiply infection of 10 pfu / cell and cells harvested 48 hours post infection. Cytoplasmic extract is prepared using 1% Triton X-100 and applied to Ni-NTA column. After washing the column with 20 mM imidazole, HcEGFR is eluted with 250 mM imidazole (at 50 mM Na ₂ HPO ₄ , pH 8.0, 300 mM NaCl). The collected fractions are dialyzed against 10 mM HEPES, pH 7.0, 50 mM NaCl, 10% glycerol, lug / ml antipain and leupetin and 0.1 mM Pefabloc SC. Proteins are frozen in dry ice / methanol and stored at -70 ° C.

Test compounds are prepared in 10 mg / ml stock in 100% dimethylsulfoxide (DMSO). Prior to the experiment, the stock solution is diluted to 500 μM with 100% DMSO and then serially diluted to the desired concentration with HEPES buffer (30 mM HEPES pH 7.4).

For the enzymatic reaction, 10 μl of each inhibitor (various concentrations) is added to each well of a 96-well plate. To this 3 μl of enzyme (1:10 dilution with 10 mM HEPES, pH 7.4, for a final concentration of 1: 120) is added. It is left on ice for 10 minutes and then 5 μl of peptide (80 μM final concentration), 10 μl of 4 × buffer (Table A), 0.25 μl of ³³ P-ATP and 12 μl of H ₂ O are added. The reaction is run at room temperature for 90 minutes and then spotted onto the P81 filter paper, which is pre-cut off the entire volume. The filter disc is washed twice with 0.5% phosphoric acid and radioactivity is measured using a liquid scintillation counter.

Reagent Final 100 Rxns 1 M HEPES pH 7.4 12.5 mM 50 μl 10 mM Na ₃ VO ₄ 50 μM 20 μl 1 M MnCl ₂ 10 mM 40 μl 1 mM ATP 20 μM 80 μl ³³ P-ATP 2.5 μCi 25 μl

Inhibition data of typical compounds of the invention are shown in Table 1 below. IC ₅₀ is the concentration of test compound required to reduce the total amount of phosphorylated substrate by 50%. The percent inhibition of the test compound is measured at at least three different concentrations and the IC ₅₀ value is evaluated from the dose response curve. % Inhibition is evaluated by the following equation:

% Inhibition Rate = 100-[CPM (Pharmaceutical) / CPM (Control)] × 100

Wherein the CPM (pharmaceutical) is in units of counts / minute and the amount of radiolabeled ATP (γ- ³³ P) introduced by the enzyme onto the RR-SRC peptide substrate after 90 minutes at room temperature in the presence of the test compound is liquid. Measured by a scintillation counter. The CPM (control) is in units of counts / minute and the liquid scintillation counter measures the amount of radiolabeled ATP (γ- ³³ P) introduced by the enzyme into the RR-SRC peptide substrate after 90 minutes at room temperature in the absence of test compounds. One value. CPM values are corrected for background counts generated by ATP in the absence of enzymatic reactions. If the IC ₅₀ value can be determined, it is recorded in Table 1, otherwise the% inhibition at 0.5 μM concentration of the test compound is shown in Table 1. Writing multiple times for the same compound means testing several times.

Inhibition of EGF-R Kinase (Recombinant Enzyme) Example IC ₅₀ (μM)% Inhibition @ 0.5 μM 173 0.5172 0.09176 0.0196> 10 697> 10 7101> 1 27111> 1 10148> 1 11115> 0.5 49167> 1 0126 .45168> 1 1127> 1 25 144> 1 14149> 1 9156> 1 34 141> 1 5.5142 > 1 24130> 1 5129> 1 6.7131> 1 0150 .0015150 0.004151> 1 34152> 1 24132> 1 0133> 1 0134> 1 35135> 1 0153> 1 14136> 1 33137 0.15

Inhibition of Epidermal Cell Kinase (ECK)

In standard pharmaceutical testing, biotinylated peptide substrates are first immobilized on neutravidin-coated microtiter plates. Appropriate buffers are then added to the fixed substrate-containing microtiter wells to maintain the test agent, epidermal cell kinase (ECK), Mg ⁺⁺ , sodium vanadate (protein tyrosine phosphatase inhibitor) and pH (7.2). ATP is then added to initiate phosphorylation. After incubation, the assay plate is washed with appropriate buffer to leave phosphorylated peptide exposed to hose radish peroxyase (HRP) -conjugated anti-phosphotyrosine monoclonal antibody. The antibody-treated plates are washed again and the HRP activity in each well is quantified as a reflection of the degree of substrate phosphorylation. This non-radioactive format is used to identify inhibitors of ECK tyrosine kinase activity, where IC ₅₀ is the concentration of drug that inhibits substrate phosphorylation by 50%. The results collected with typical compounds of the present invention are listed in Table 2. Writing multiple times for a given compound means testing it several times.

Inhibition of kinase insertion domain containing receptors (KDR: catalytic domain of VEGF receptors)

In this standard pharmaceutical test procedure, the substrate peptide (copolymer of glutamic acid and tyrosine, E: Y :: 4: 1) and Mg ⁺⁺ and sodium vanadate (protein) will phosphorylate the KDR protein in the presence or absence of an inhibitor compound. And other cofactors such as tyrosine phosphatase inhibitors) in a suitable buffer to maintain pH (7.2). Phosphorylation is then initiated by the addition of ATP and radiotracer (P ³² -or P ³³ -labeled ATP). After incubation, the radioactive phosphate combined with the acid-insoluble fraction of the assay mixture is then quantified as a reflection of the substrate phosphorylation. This radioactivity format is used to identify inhibitors of KDR tyrosine kinase activity, where IC ₅₀ is the concentration of drug that inhibits substrate phosphorylation by 50%. The results collected with typical compounds of the present invention are listed in Table 2. Writing multiple times for a given compound means testing it several times.

Mitosis Activated Protein Kinase (MAPK) Assay

To assess inhibitors of MAP (mitotic substance activating protein) kinases, a two-component coupling standard pharmaceutical test procedure, which measures the phosphorylation of serine / threonine residues at the appropriate sequence in the substrate in the presence and absence of putative inhibitors, is carried out. Used. Recombinant human MEK 1 (MAPKK) is first used to activate recombinant human ERK2 (MAPK) and activated MAPK (ERK) is used as a substrate (MBP peptide or MYC peptide in the presence of ATP, Mg ⁺² and radiolabeled ³³ P ATP). Incubate with). Phosphorylated peptides are captured on washed P81 phosphocellulose filters (embedded in paper filters or microtiter plates) and counted by scintillation.

Peptide substrates used for analysis are MBP, peptide substrate (APRTPGGRR) or synthetic Myc substrate (KKFELLPTPPLSPSRR.5 TFA). Recombinant enzymes used are prepared as GST fusion proteins of human ERK 2 and human MEK1. Inhibitor samples are prepared with 10 × stocks in 10% DMSO and appropriately used to deliver 10 μg / ml for single point screening administration or 100, 10, 1 and 0.1 μM final concentrations for dose response curves. The final DMSO concentration is below 1%.

The reaction is carried out as follows with 50 μl of reaction volume in 50 mM Tris Kinase buffer, pH 7.4. Appropriate volumes of kinase buffer and inhibitor sample are added to the tube. Appropriate dilutions of the enzyme are carried to produce 2-5 μg recombinant MAPK (Erk) per tube. Inhibitors are incubated with MAPK (Erk) at 0 ° C. for 30 minutes. Erk is activated by addition of recombinant Mek (MAPKK) (0.5-2.5 μg) or fully activated Mek (0.05-0.1 units) and incubated at 30 ° C. for 30 minutes. Subsequent addition of substrate and gamma ³³ P ATP gave a final concentration of 0.5-1 mM MBPP or 250-500 μM Myc; 0.2-0.5 μCi gamma P 33 ATP / tube; Achieve a 50 μM ATP final concentration. Samples are incubated at 30 ° C. for 30 minutes and the reaction is stopped by adding 25 μl of ice-cold 10% TCA. After cooling the sample on ice for 30 minutes, 20 μl of the sample is transferred onto P81 phosphocellulose filter paper or a suitable MTP embedded with P81 filter. The filter paper or MTP is washed twice with a large amount of 1% acetic acid followed by twice with water. Filter or MTP is briefly air dried before addition of scintillation and samples are counted in a suitable scintillation counter equipped to read ³³ P isotopes. Samples were positive controls (activated enzyme and substrate); Reactive cow control group; Mineral control; Samples having different concentrations of putative inhibitors; And samples with comparative inhibitors (other active compounds or non-specific inhibitors such as staurosporin or K252 B).

Convert raw data to cpm. Sample duplicates are averaged and corrected for background count. The mean cpm data is tabulated and the percentage inhibition by the test compound is calculated as (corrected cpm control-corrected cpm sample / control) × 100 =% inhibition. When several concentrations of inhibitors are tested, IC ₅₀ values (concentrations that provide 50% inhibition) are determined graphically from the dose response curves of percent inhibition or by a suitable computer program. The results collected for typical compounds of the invention are listed in Table 2 and there may be multiple entries for the same compound; This means that the compound has been evaluated at least once.

Table 2a

Inhibition of kinase insertion domain containing receptors (KDR), epidermal cell kinase (Eck) and mitotic substance activating protein kinase (Mek-Erk)

Table 2b

Inhibition of kinase insertion domain containing receptors (KDR), epidermal cell kinase (Eck) and mitotic substance activating protein kinase (Mek-Erk)

Table 2c

Inhibition of kinase insertion domain containing receptors (KDR), epidermal cell kinase (Eck) and mitotic substance activating protein kinase (Mek-Erk)

Table 2d

Inhibition of kinase insertion domain containing receptors (KDR), epidermal cell kinase (Eck) and mitotic substance activating protein kinase (Mek-Erk)

Inhibition of cancer cell growth measured by cell number

Human tumor cell lines are plated in RPMI 1640 medium containing 5% FBS (fetal bovine serum) in 96-well plates (250 μl / well, 1-6 × 10 ⁴ cells / ml). 24 hours after plating, test compounds are added at 5 log concentration (0.01-100 mg / mL) or at lower concentrations for more potent compounds. 48 hours after exposure to test compounds, cells are fixed with trichloroacetic acid and stained with Sulforhodamine B. After washing with trichloroacetic acid, the binding dye is dissolved in 10 mM Tris base and the optical density is measured using a plate reader. Under assay conditions, optical density is proportional to the number of cells in the well. IC ₅₀ (concentration causing 50% inhibition of cell growth) is determined from the growth inhibition plot. The testing process was conducted by Philip Skehan et. al, J. Natl. Canc. Inst., 82, 1107-1112 (1990). These data are shown in Table 3 below. Information on some of the cell lines used in this test procedure is available from American Type Tissue Collection: Cell Lines and Hybridomas, 1994 Reference Guide, 8th Edition.

Inhibition of cancer cell growth measured by cell number (IC ₅₀ μg / ml) MDA-MB-Example 435 A431 SK-BR3 A2780 DDP SW620 3T3 3T3 / c-erbb2 99 0.020 0.025 0.016 0.032 0.036 0.033 100 0.067 0.369 0.429 0.270 0.249 0.325 101 0.073 0.216 0.18 0.231 0.313 0.326 101 0.365 0.123 0.0374 0.286 1.53 0.933 102 0.490 1.309 0.780 1.491 3.054 2.18103 0.309 1.611 0.767 2.391 2.690 2.637 104 0.021 0.049 0.034 0.044 0.107 0.207 106 0.245 0.270 0.281 10 10 1.961> 5> 5> 5> 5107> 5> 5> 5> 5> 5> 5108 0.352 0.342 0.294 <.0005 0.525 0.0198109> 5> 5> 5 2.922> 5 4.616 110 0.0280 0.0244 0.0281 0.0181 0.0923 0.0311111 3.404> 5> 5 1.565> 5 3.301 112 0.0033 0.257 0.336 0.146 0.392 0.251115 0.0359 0.0368 0.0220 0.0212 0.344 0.0267126 2.626 0.786 2.094 4.313 3.219 4.801127> 5> 5> 5> 5> 5> 5

Inhibition of Growth of Human Colon Carcinoma SW620 in Vivo

Typical compounds of the present invention (listed below) are evaluated by standard in vivo pharmaceutical test procedures that measure their ability to inhibit the growth of human epidermal tumors. Human colon carcinoma SW620 cells (American Type Culture Collection, Rockville, Maryland # CCL-227) are allowed to grow in vitro as described above. BALB / c nu / nu female mice (Charles River, Wilmington, Mass.) Are used in standard pharmaceutical test procedures in vivo. SC is injected into mice with 7 × 10 ⁶ cell units. Once tumors have a mass of 80-120 mg, mice are randomized into treatment groups (day 0). Mice are IP treated once daily over 1 to 20 days after staging at a dose of 30, 10, 3 or 1 mg / kg / dose to be evaluated in 0.2% Klucel. Control animals only receive vehicle. Tumor mass is measured in [(length × width ² ) / 2] every 7 days after staging for 28 days. Relative tumor growth (tumor mass mean at 7, 14, 21 and 28 divided by mean tumor mass at day 0) is determined for each treatment group. Statistical analysis of log relative tumor growth (Student-t-test) compares treatment group versus control group. p-value (p 0.05) shows a statistically significant decrease in relative tumor growth in the treatment group compared to the vehicle control group.

The compound of Example 99 is evaluated for its ability to inhibit the growth of human colon carcinoma in vivo using the standard pharmaceutical test procedures described above. The collected results are shown in Table 4.

In vivo inhibition of human colon carcinoma SW620 (9791CD-186) by the compound of Example 99 in mice. Relative tumor growth a b c d b c d b c d e Pharmaceutical treatment mg / kg / dose dose 7 days % T / C (p) 14 days % T / C (p) 21st % T / C (p) S / T Klucel (Placebo) 4.10 11.59 11.23 13/15 Example 99 (30 IP) 1.81 44 <0.01 3.85 33 <0.01 4.44 40 0.02 4/5 Example 99 (10 IP) 3.69 90 0.37 7.88 68 0.18 9.75 87 0.36 5/5 Example 99 (3 IP) 3.80 93 0.62 12.53 108 0.78 16.47 147 0.54 5/5 a) Compound administered IP over 1 to 20 days b) Relative tumor growth = Tumor mass mean on days 7, 14 and 21 Mean mass mean on day 0 c)% T / C = Relative tumor growth in treatment group × 100 Relative mass growth of placebo group d) Statistical analysis of log relative tumor growth (Student-t-test). The p-value (p = 0.05) represents a statistically significant decrease in the relative mass growth of the treatment group compared to the placebo control group. e) S / T = number of treatments +21 days after staging / tumor staging

As shown in Table 4, the compound of Example 99 inhibits tumor growth; For example, 30 mg / kg (administered i.p. for 1-20 days) inhibits tumor growth by 56% on day 7, 67% on day 14 and 60% on day 21.

Based on the results collected with typical compounds of the present invention, the compounds of the present invention are anti-neoplastic agents useful for the treatment of neoplasms, inhibition of their growth or eradication thereof. In particular, the compounds of the invention are useful for the treatment of, growth inhibition or eradication of EGFR expressing EGFR such as those of the breast, kidney, bladder, oral cavity, larynx, esophagus, stomach, colon, ovary or lung. In addition, the compounds of the present invention are useful for treating, inhibiting growth or eradicating neoplasms of the breast expressing receptor proteins produced by the erbB2 (Her2) tumor gene. Based on the results collected, the compounds of the present invention are also useful for the treatment of cysticosins.

The compounds of the present invention may be formulated without watering or combined with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like may be tablets, capsules, dispersible powders, granules or suspensions containing, for example, about 0.05 to 5% suspending agent, for example syrups containing about 10 to 50% sugars and examples For example, it may be administered orally in the form of elixirs containing about 20-50% of ethanol, or parenterally in the form of a suspension containing about 0.05-5% of a suspending agent in a sterile injectable solution or isotonic medium. Such pharmaceutical preparations may contain, for example, about 0.05 to about 90 weight percent, more typically about 5 to 60 weight percent of the active ingredient in combination with the carrier.

The effective dosage of the active ingredient used may vary depending on the specific compound used, the method of administration and the severity of the condition to be treated. In general, however, satisfactory results are achieved when a daily dose of about 0.5 to about 1000 mg / kg body weight of a compound of the invention is administered, optionally divided into two to four times a day, or in continuous release form. The total daily amount is planned to be about 1 to 1000 mg, preferably about 2 to 500 mg. Suitable dosage forms for oral administration include from about 0.5 to 1000 mg of the active compound in direct mixture with a pharmaceutically acceptable solid or liquid carrier. This dosing regimen may be adjusted to provide the optimum therapeutic response. For example, multiple separated doses may be administered daily or the dose may be proportionally reduced depending on the exigencies of the therapeutic situation.

The compounds of the present invention can be administered by oral and intravenous, intramuscular or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycol, non-ionic surfactants and edible oils such as corn oil, peanut oil and sesame oil. And according to the nature of the active ingredient and the particular dosage form desired. Adjuvants commonly used in the preparation of pharmaceutical compositions may advantageously include flavoring agents, colorants, preservatives and antioxidants such as vitamin E, ascorbic acid, BHT and BHA.

Preferred pharmaceutical compositions in terms of ease of preparation and administration are solid compositions, especially tablets and light-filled or liquid-filled capsules. Oral administration of the compound is preferred.

In some cases it may be desirable to administer the compound directly to the airways in the form of aerosols.

The compounds of the present invention can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds, such as free bases or pharmaceutically acceptable salts, can be prepared in water, suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterilized and fluid to the extent that easy injection is possible. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (eg glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof and vegetable oils.

For the treatment of cancer, the compounds of the present invention can be administered in conjunction with other anti-tumor substances or radiation therapy. These other substances or radiotherapy may be provided at the same time or at different times as the compounds of the present invention. These combination therapies can be synergistic and lead to improved efficacy. For example, the compounds of the present invention may be selected from mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cisplatin or cyclophosphamide, anti-metabolic agents such as 5-fluorouracil or hydroxyurea, adriamycin or bleomycin DNA intercalators, topoisomerase inhibitors such as etoposide or captothecin, antiangiogenic agents such as angiostatin, and antiestrogens such as tamoxifen.

Typical preparation methods of the compounds of the present invention are described below.

Example 1

1,4-dihydro-7-methoxy-4-oxo-quinoline-3-carbonitrile

A mixture of 30.2 g (245.2 mmol) of 3-methoxy aniline and 41.5 g (245.2 mmol) of ethyl (ethoxymethylene) cyanoacetate is heated to 140 ° C. for 30 minutes in the absence of solvent. To the resulting oil is added 1200 ml of Dowtherm. The solution is refluxed under nitrogen for 22 hours with stirring. The mixture is cooled to room temperature and the solids collected and washed with hexanes. The solid was recrystallized from acetic acid to give 17 g of 1,4-dihydro-7-methoxy-4-oxo-quinoline-3-carbonitrile: mass spectrum (electrospray, m / e): M + H 200.9 .

Example 2

1,4-dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile

To a suspension of 10 g (49.6 mmol) of 1,4-dihydro-7-methoxy-4-oxo-quinoline-3-carbonitrile in 160 ml of trifluoroacetic anhydride, add 6 g (74.9 mmol) of ammonium nitrate to 3 Add over time. The mixture is stirred for another 2 hours. Excess anhydride is removed at 45 ° C. under reduced pressure. The residue is stirred with 500 ml of water. The solids are collected and washed with water. The solid is dissolved in 1000 ml of boiling acetic acid and the solution is treated with bleached charcoal. The mixture is filtered and concentrated to 300 ml volume. On cooling the solids are collected and 5.4 g of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile are obtained as a brown solid: mass spectrum (electrospray, m / e ): M + H 246.

Example 3

4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile

A mixture of 5.3 g (21.6 mmol) of 1,4-dihydro-7-methoxy-6-nitro-4-oxo-quinoline-3-carbonitrile and 9 g (43.2 mmol) of phosphorus pentachloride was 165 for 2 hours. Heat at 캜. Dilute the mixture with hexanes and collect the solids. The solid is dissolved in 700 ml of ethyl acetate and washed with dilute cold sodium hydroxide solution. The solution is dried over magnesium sulphate and filtered through a pad of silica gel to give 5.2 g of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile as a tan solid.

Example 4

2-cyano-3- (4-nitrophenylamino) acrylic acid ethyl ester

4-nitroaniline (60.0 g, 0.435 mol) and ethyl (ethoxymethylene) cyanoacetate (73.5 g, 0.435 mol) are mechanically mixed in the flask. After the mixture has melted and reshaped, it is heated at 100 ° C. for 0.5 h. 114 g fractions of the crude product are recrystallized from dimethylformamide to give 44.2 g of yellow crystals: mp 227-228.5 ° C.

Example 5

1,4-dihydroquinoline-6-nitro-4-oxo-3-carbonitrile

A slurry of 25.0 g (95.8 mmol) of 2-cyano-3- (4-nitrophenylamino) acrylic acid ethyl ester in 1.0 L of Dowtherm A is heated at 260 ° C. under N ₂ for 12.5 hours. The cold reaction mixture is poured into 1.5 L of hexane. The product is collected, washed with hexane and hot ethanol and dried in vacuo. 18.7 g of a brown solid are obtained. Analytical samples are obtained by recrystallization from dimethylformamide / ethanol: mass spectrum (electrospray, m / e): M + H 216.

Example 6

4-chloro-6-nitro-quinoline-3-carbonitrile

A mixture of 31.3 g (0.147 mol) of 6-nitro-4-oxo-1,4-dihydro-quinoline-3-carbonitrile and 160 ml of phosphorus oxychloride was refluxed for 5.5 h. Phosphorus oxychloride is removed in vacuo and the residue is poured onto ice and neutralized with sodium bicarbonate. The product is collected, washed with water and dried in vacuo (50 ° C.). 33.5 g of a tan solid are obtained; Solids: mass spectrum (electrospray, m / e): M + H 234.

Example 7

2-cyano-3- (2-methyl-4-nitrophenyl) acrylic acid ethyl ester

A mixture of 2-methyl-4-nitroaniline (38.0 g, 250 mmol), ethyl (ethoxymethylene) cyanoacetate (50.8 g, 300 mmol) and 200 ml of toluene was refluxed for 24 hours, cooled and 1: Dilute with 1 ether-hexane and filter. The resulting white solid is washed with hexane-ether and dried to give 63.9 g, mp 180-210 ° C.

Example 8

1,4-dihydroquinoline-8-methyl-6-nitro-3-carbonitrile

A stirring mixture of 64 g (230 mmol) of 2-cyano-3- (2-methyl-4-nitrophenyl) acrylic acid ethyl ester and 1.5 L of Dowtherm A was heated at 260 ° C. for 12 h, cooled and diluted with hexane Then filtered. The gray solid thus obtained is washed with hexane and dried to give 51.5 g, mp 295-305 ° C.

Example 9

4-chloro-8-methyl-6-nitro-quinoline-3-carbonitrile

A stirred mixture of 1,4-dihydroquinoline-8-methyl-6-nitro-3-carbonitrile (47 g, 200 mmol) and 200 ml of phosphorus oxychloride was refluxed for 4 hours. Phosphorus oxychloride is removed in vacuo and the residue is stirred with methyl chloride at 0 ° C. and then treated with a slurry of ice and sodium carbonate. The organic layer is separated and washed with water. The solution is dried and concentrated to 700 ml volume. The product is precipitated by the addition of hexanes and cooled to 0 ° C. The white solid is filtered and dried to give 41.6 g, mp 210-212 ° C.

Example 10

7-ethoxy-4-hydroxy-quinoline-3-carbonitrile

A mixture of 10 g (73 mmol) of 3-ethoxy aniline and 12.3 g (73 mmol) of ethyl (ethoxymethylene) cyanoacetate is heated in 90 ml of Dowther at 140 ° C. for 7 hours. To this mixture is added 250 ml of Dowther. The solution is stirred and periodically distilled to reflux for 12 hours under nitrogen while removing ethanol. The mixture is cooled to room temperature, the solids collected and washed with hexanes. The crude solid was treated with boiling ethanol and then filtered to give 9.86 g of a brown solid: mass spectrum (electrospray, m / e): M + H 214.7.

Example 11

7-ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile

To a suspension of 5 g (23 mmol) of 7-ethoxy-4-hydroxy-quinoline-3-carbonitrile in 75 ml of trifluoroacetic anhydride, 5.5 g (69 mmol) of ammonium nitrate were added over 6 hours at room temperature do. Excess anhydride is removed at 45 ° C. under reduced pressure. The residue is stirred with 300 ml of water. The solids were collected and treated with boiling ethanol to yield 3.68 g of tin solids: mass spectrum (electrospray, m / e) M + H 259.8.

Example 12

4-chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile

A mixture of 3.45 g (13 mmol) of 7-ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 5.55 g (26 mmol) of phosphorus pentachloride and 10 ml of phosphorus oxychloride was added for 3 hours. Reflux. Dilute the mixture with hexanes and collect the solids. The solid is dissolved in 500 ml of ethyl acetate and washed with dilute cold sodium hydroxide solution. The solution is dried over magnesium sulphate and filtered through a pad of silica gel. Remove the solvent to afford 2.1 g of beige solid: mass spectrum (electrospray, m / e) M + H 277.7.

Example 13

8-methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile

A mixture of 12.6 g (75 mmol) of 2-methoxy-4-nitroaniline and 12.7 g (75 mmol) of ethyl (ethoxymethylene) cyanoacetate was heated in 100 ml of Dowther at 120 ° C. overnight and at 180 ° C. for 20 hours. do. 300 ml of Dowther is added to this mixture. The solution is stirred and periodically distilled to reflux for 12 hours under nitrogen while removing ethanol. The mixture is cooled to room temperature, the solids collected and washed with hexanes. The crude solid was treated with boiling ethanol and then filtered to give 12 g of a brown solid: mass spectrum (electrospray, m / e): M + H 245.8.

Example 14

4-chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile

A mixture of 4 g (16 mmol) of 8-methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g (32 mmol) of phosphorus pentachloride and 15 mL of phosphorus oxychloride was added for 2.5 hours. Reflux. The mixture is diluted with hexanes and the solids collected. The solids are dissolved in 500 ml of ethyl acetate and washed with dilute cold sodium hydroxide solution. The solution is dried over magnesium sulphate and filtered through a pad of silica gel. Remove the solvent to afford 2.05 g of a tan solid: mass spectrum (electrospray, m / e) M + H 263.7.

Example 15

4-Chloro-but-2-yanoic acid

Propargyl chloride (2 mL, 26.84 mmol) is dissolved in 40 mL tetrahydrofuran under nitrogen and cooled to -78 ° C. After addition of n-butyllithium (5.4 mL, 13.42 mmol, 2.5 M in n-hexane) and stirring for 15 minutes, a stream of dry carbon dioxide is passed through it at -78 ° C for 2 hours. The reaction solution is filtered and neutralized with 3.5 ml of 10% sulfuric acid. After evaporation of the solution, the residue is extracted with ether. The ether solution is washed with saturated brine solution and dried over sodium sulphate. After evaporation of the dry ether solution, 0.957 g (60%) of oil product are obtained: ESMS m / z 116.6 (MH ⁺ ).

Example 16

4-Dimethylamino-but-2-yanoic acid

N-butyl lithium in hexanes (96 mL, 2.5 M in n-hexane) is added slowly under nitrogen to 1-dimethylamino-2-propyne (20 g, 240 mmol) in 100 mL of tetrahydrofuran. The mixture is stirred for 1 h at -78 ° C and then passed through dry carbon dioxide overnight. The resulting solution is poured into water and washed with ethyl acetate. The aqueous layer is evaporated under reduced pressure to give crude acid. The dry acid is dissolved in methanol and the insoluble salts are removed by filtration. Collect the filtrate and dry in vacuo to give 15.6 g of 4-dimethylamino-but-2-inoic acid: mass spectrum (m / e): M-H 126.

Example 17

Bis- (2-methoxy-ethyl) -prop-2-ynyl-amine

Propargyl bromide (17.8 g, 150 mmol) is added dropwise to a mixture of bis (2-methoxy-ethyl) amine (20 g, 150 mmol) and cesium carbonate (49 g, 150 mmol) in 350 ml of acetone. The mixture is stirred overnight at room temperature under nitrogen. The inorganic salt is then filtered off and the solvent is removed. The residue is dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract is then evaporated to yield 20 g of bis- (2-methoxy-ethyl) -prop-2-ynyl-amine: mass spectrum (m / e): M + H 172.

Example 18

4- [bis- (2-methoxy-ethyl) -amino] -but-2-inoic acid

N-butyl lithium in hexanes (42 mL, 2.5 M in n-hexane) bis- (2-methoxy-ethyl) -prop-2-ynyl-amine (18 g, 105 mmol) in 80 mL tetrahydrofuran Is added slowly under nitrogen. The mixture is stirred for 1 h at -78 ° C and then passed through dry carbon dioxide overnight. The resulting solution is poured into water and washed with ethyl acetate. The aqueous layer is evaporated under reduced pressure to give crude acid. The dry acid is dissolved in methanol and the insoluble salts are removed by filtration. Collect the filtrate and dry in vacuo to afford 18 g of 4- [bis- (2-methoxy-ethyl) -amino] -but-2-inoic acid: mass spectrum (m / e): M-H 214.

Example 19

1-Methyl-4-prop-2-ynyl-piperazine

Propargyl bromide (23.8 g, 200 mmol) is added dropwise to a mixture of 1-methyl-piperazine (20 g, 200 mmol) and cesium carbonate (65 g, 200 mmol) in 350 ml of acetone. The mixture is stirred overnight at room temperature under nitrogen. The inorganic salt is then filtered off and the solvent is removed. The residue is dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract is then evaporated to yield 7.5 g of 1-methyl-4-prop-2-ynyl-piperazine: mass spectrum (m / e): M + H 139.

Example 20

4- (4-Methyl-piperazin-1-yl) -but-2-inoic acid

N-butyl lithium in hexane (17.2 mL, 2.5 M in n-hexane) was slowly added to 1-methyl-4-prop-2-ynyl-piperazine (6.0 g, 43.5 mmol) in 40 mL of tetrahydrofuran under nitrogen. Add. The mixture is stirred for 1 h at -78 ° C and then passed through dry carbon dioxide overnight. The resulting solution is poured into water and washed with ethyl acetate. The aqueous layer is evaporated under reduced pressure to give crude acid. The dry acid is dissolved in methanol and the insoluble salts are removed by filtration. Collect the filtrate and dry in vacuo to afford 7 g of 4- (4-methyl-piperazin-1-yl) -but-2-inoic acid: mass spectrum (m / e): M-H 181.

Example 21

(2-methoxy-ethyl) -methyl-prop-2-ynyl-amine

Propargyl bromide (26.8 g, 225 mmol) is added dropwise to a mixture of N- (2-methoxyethyl) methyl amine (20 g, 225 mmol) and cesium carbonate (73 g, 225 mmol) in 350 ml of acetone. The mixture is stirred overnight at room temperature under nitrogen. The inorganic salt is then filtered off and the solvent is removed. The residue is dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract is then evaporated to afford 14 g of (2-methoxy-ethyl) -methyl-prop-2-ynyl-amine: mass spectrum (m / e): M + H 127.

Example 22

4-[(2-Methoxy-ethyl) -methyl-amino] -but-2-inoic acid

N-butyl lithium in hexane (37.8 mL, 2.5 M in n-hexane) (2-methoxy-ethyl) -methyl-prop-2-ynyl-amine (12.0 g, 94.5 mmol) in 90 mL tetrahydrofuran Is added slowly under nitrogen. The mixture is stirred for 1 h at -78 ° C and then passed through dry carbon dioxide overnight. The resulting solution is poured into water and washed with ethyl acetate. The aqueous layer is evaporated under reduced pressure to give crude acid. The dry acid is dissolved in methanol and the inorganic salts are removed by filtration. Collect the filtrate and dry in vacuo to give 15 g of 4-[(2-methoxy-ethyl) -methyl-amino] -but-2-inoic acid: mass spectrum (m / e): M-H 170.

Example 23

Allyl-methyl-prop-2-ynyl-amine

Propargyl bromide (33.4 g, 281 mmol) is added dropwise to a mixture of isopropyl-methyl-amine (20 g, 281 mmol) and cesium carbonate (90 g, 281 mmol) in 350 ml of acetone. The mixture is stirred overnight at room temperature under nitrogen. The inorganic salt is then filtered off and the solvent is removed. The residue is dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract is then evaporated to yield 4.6 g of allyl-methyl-prop-2-ynyl-amine: mass spectrum (m / e): M + H 110.

Example 24

4- (Allyl-methyl-amino) -but-2-inoic acid

N-butyl lithium in hexanes (16.4 mL, 2.5 M in n-hexane) is added slowly under nitrogen to allyl-methyl-prop-2-ynyl-amine (4.5 g, 46 mmol) in 50 mL of tetrahydrofuran. The mixture is stirred at −78 ° C. for 1 hour and then passed through dry carbon dioxide overnight. The resulting solution is poured into water and washed with ethyl acetate. The aqueous layer is evaporated under reduced pressure to give crude acid. The dry acid is dissolved in methanol and the insoluble salts are removed by filtration. Collect the filtrate and dry in vacuo to yield 4.1 g of 4- (allyl-methyl-amino) -but-2-inoic acid: mass spectrum (m / e): M-H 152.

Example 25

4-methoxymethoxy-but-2-inoic acid

To a suspension of 8.2 g of 60% sodium hydride in mineral oil in 271 ml of tetrahydrofuran, 10 g of propargyl alcohol was added dropwise over 15 minutes with stirring at 0 ° C. under nitrogen. The mixture is stirred for another 30 minutes. To the stirred mixture 15.8 g of chloromethylmethyl ether is added at 0 ° C. Stirring is continued overnight at room temperature. The mixture is filtered and the solvent is removed from the filtrate. The residue is distilled off (35-38 ° C., 4 mm) to give 8.5 g of liquid. The distillate is dissolved in 200 ml of ether. The solution is stirred under nitrogen and cooled to −78 ° C. with 34.1 mL of 2.5 mol n-butyl lithium in hexanes added over 15 minutes. Stirring is continued for 1.5 hours. Dry carbon dioxide is passed to the surface of the stirred reaction mixture while warming to room temperature at -78 ° C. The mixture is stirred overnight under a carbon dioxide atmosphere. The mixture is poured into a mixture of 14 ml hydrochloric acid and 24 ml water. The organic layer is separated and dried over magnesium sulphate. The solvent is removed and the residue is kept at 100 ° C., 4 mm for 1 hour to give 10.4 g of 4-methoxymethoxy-but-2-inoic acid.

Example 26

4-bromo crotonic acid

Braun [Giza Braun, J. Am. Chem. Soc. 52, 3167 (1930)], 11.76 mL (17.9 g, 0.1 mol) of methyl 4-bromo crotonate in 32 mL of ethanol and 93 mL of water is cooled to -11 ° C. The reaction mixture is vigorously stirred and 15.77 g (0.05 mol) of fine powder barium hydroxide is added in portions over about 1 hour. Cooling and vigorous stirring are continued for about 16 hours. The reaction mixture is then extracted with 100 ml of ether. The aqueous layer is treated with 2.67 mL (4.91 g; 0.05 mol) of concentrated sulfuric acid. The resulting mixture is extracted into 3-100 mL fractions of ether. The combined etheric extracts are washed with 50 ml brine and then dried over sodium sulfate. The solution is taken up in oil in vacuo. This oil is taken up in about 400 ml of boiling heptane, leaving a rubber. Heptane solution is separated and boiled to about 500 ml. Cooling yields 3.46 g of product.

Example 27

4- (2-Methoxy-ethoxy) -but-2-inoic acid

To a suspension of 6.04 g (151 mmol) of 60% sodium hydride in 200 mL of tetrahydrofuran is added 10 g (131.4 mmol) of 2-methoxyethanol dropwise at 0 ° C. over 15 minutes. After 1 hour, 19.54 g (131.4 mmol) of 80% propargyl bromide are added dropwise. After stirring for 17 hours at room temperature, the mixture is filtered and the solvent is removed. The residue is distilled off (48-51 ° C., 4 mm) to give 11.4 g of a colorless liquid. It is dissolved in 250 ml of ether and cooled to -78 ° C with stirring under nitrogen. To this solution was added dropwise 39.95 mL (99.9 mmol) of a 2.5 M n-butyl lithium solution in hexane over 15 minutes. After 1.5 hours, the mixture is slowly warmed to room temperature while bubbling dry carbon dioxide. The mixture is kept overnight in a carbon dioxide atmosphere. To the mixture is added 100 ml of 3 N hydrochloric acid and solid sodium chloride. The organic layer is separated and dried over magnesium sulphate. The solvent is removed and the residue is kept in vacuo to give 11.4 g of the title compound: mass spectrum (electrospray, m / e, negative mode): M-H 156.8.

Example 28

4- (methoxymethoxy) -but-2-inoic acid

To a suspension of 8.2 g (205 mmol) of 60% sodium hydride in 271 mL of tetrahydrofuran is added dropwise 10.0 g (178.4 mmol) of propargyl alcohol at 0 ° C. with stirring. After 30 minutes, 15.8 g (196.2 mmol) of chloromethylmethyl ether are added. After stirring over the weekend at room temperature, the mixture is filtered and the solvent is removed. The residue is distilled off (35-38 ° C., 4 mm) to give 8.54 g of a colorless liquid. It is dissolved in 200 ml of ether and cooled to -78 ° C with stirring under nitrogen. To this solution was added dropwise 34.1 mL (85.3 mmol) of a 2.5 M n-butyl lithium solution in hexane over 15 minutes. After 1.5 hours, the mixture is slowly warmed to room temperature while bubbling dry carbon dioxide. The mixture is kept overnight in a carbon dioxide atmosphere. To the mixture is added 14 ml hydrochloric acid in 24 ml water. The organic layer is separated and dried over magnesium sulphate. The solvent is removed and the residue is kept in vacuo to yield 10.4 g of the title compound as a liquid.

Example 29

4-((2S) -2-methoxymethylpyrrolidin-1-yl) butinoic acid

Of n- hexane solution of butyllithium (35.9 mmol) 100 ㎖ THF ( 2S) -2- methoxymethyl-1-prop-2-pyrrolidine is nilpi N ₂ and a solution of 5.49 g (35.9 mmol) - Add at 78 ° C. over 10 minutes. After low temperature stirring for 1 hour, CO ₂ is bubbled into the solution while slowly warming to 25 ° C. After stirring overnight, 100 ml of water are added, the reaction mixture is extracted with ethyl acetate and the extract is discarded. The reaction mixture is adjusted to pH 7 with 20% H ₂ SO ₄ and then the solvent is removed. The residue is slurried with methanol and filtered. The filtrate was evaporated and dried in vacuo to give 7.06 g of 4-((2S) -2-methoxymethylpyrrolidin-1-yl) butinoic acid as brown foam: mass spectrum (electrospray, m / e): M + H 198.0.

Example 30

(2S) -2-methoxymethyl-1-prop-2-ynylpyrrolidine

A mixture of 4.82 g (41.9 mmol) of S-2- (methoxymethyl) pyrrolidine, 13.7 g (41.9 mmol) of cesium carbonate and 5.00 g (41.9 mmol) of propargyl bromide in 80 ml of acetone is stirred overnight at 25 ° C. . The reaction mixture is filtered and the solvent is removed from the filtrate. The residue is diluted with water and a small amount of saturated NaHCO ₃ and extracted with ether. The extract was treated with Darco, dried and evaporated to give 5.93 g of (2S) -2-methoxymethyl-1-prop-2-ynylpyrrolidine as orange yellow oil: mass spectrum (electrospray, m / e): 153.8.

Example 31

4- (1,4-dioxa-8-azaspiro [4.5] deck-8-yl) but-2-inoic acid

10.1 g (55.8 mmol) of n-butyllithium (55.8 mmol) in hexane with 3- (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) but-2-yn in 185 mL THF To the solution is added dropwise at -78 ° C under N ₂ . After 1 hour of stirring at -78 ° C, the solution is bubbled with CO ₂ while slowly warming to 25 ° C. After stirring overnight, the reaction mixture is diluted with 150 mL of water, extracted with ethyl acetate and the extract is discarded. The solution is adjusted to pH 6 with 2 M sulfuric acid and then evaporated. The residue is slurried with methanol and filtered. Evaporate the filtrate and evaporate in vacuo to give 4.5 g of 4- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) but-2-inoic acid as a brown amorphous replacement: mass Spectrum (electrospray, m / e): M + H 225.8.

Example 32

3- (1,4-dioxa-8-azaspiro [4,5] deck-8-yl) but-2-yne

A mixture of 10.0 g (69.9 mmol) of 1,4-dioxa-8-azaspiro [4,5] decane, 22.8 g (69.9 mmol) of cesium carbonate and 8.32 g (69.9 mmol) of propargyl bromide in 165 ml of acetone was added. Stir overnight at ° C. The reaction mixture is filtered and the filtrate is evaporated to dryness. A small amount of water and saturated NaHCO ₃ is added to the residue and it is extracted with ether. The ethereal extract was treated with Darco, dried and evaporated to give 10.8 g of 3- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) but-2-yne as an orange yellow oil. Obtained as: Mass spectrum (electrospray, m / e): M + H 181.8.

Example 33

Methyl 4-benzyloxy-2- (dimethylaminomethyleneamino) -5-methoxybenzoate

A stirring mixture of 70.0 g (244 mmol) of methyl 2-amino-4-benzyloxy-5-methoxybenzoate (Phytochemistry 1976, 15, 1095) and 52 ml of dimethylformamide dimethyl acetal was heated at 100 ° C. for 1.5 hours , Cooled and then directly evaporated under high vacuum to give 81.3 g of an off-white solid, mp 134-140 ° C .; NMR (CDCl ₃ ) d 3.01 (s, Me ₂ N).

Example 34

7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile

To a stirred solution of 26.9 ml of n-butyllithium (2.5 M in hexane) in 50 ml of THF, 3.51 ml of acetonitrile in 20 ml of THF are added at −78 ° C. for 10 minutes. After stirring at −78 ° C. for 30 minutes, the mixture is treated with 10 g of methyl 4-benzyloxy-2- (dimethylaminomethyleneamino) -5-methoxybenzoate for 5 minutes in 20 ml of THF. After 15 minutes at −78 ° C. the stirred mixture is further warmed to 0 ° C. for 30 minutes. Then treat with 5 ml of acetic acid, warm to 25 ° C. and stir for 30 minutes. The mixture is evaporated to dryness and diluted with aqueous sodium bicarbonate. The resulting off-white solid is filtered off and washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile are obtained as off-white solid, dec> 255 ° C .; Mass spectrum (electrospray, m / e) M + H 307.

Example 35

7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile

5 ml of oxalyl chloride (2 M in methylene chloride) and N, N-dimethyl in a stirred suspension of 1 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile in 10 ml of methylene chloride Add 2 drops of formamide. The mixture is refluxed for 20 minutes and aqueous sodium bicarbonate is added slowly thereto until bubbling stops. After separating the layers, the organic layer is evaporated to a small volume and then passed through a plug of magnesol. Elution with 50 ml of methylene chloride and then evaporation gave 0.6 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as a pale yellow solid, mp 282-284 ° C .; Mass spectrum (electrospray, m / e) M + H 325.

Example 36

4-Chloro-7-hydroxy-6-methoxy-quinoline-3-carbonitrile

A stirred suspension of 0.54 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile in 10 ml of methylene chloride is cooled to 0 ° C. To this 10 ml of boron trichloride (1 M in methylene chloride) is added. As warming to room temperature the mixture darkens and solids precipitate. After stirring for 1 hour, no further reaction was observed. The solids (unreacted starting material) are filtered off and the remaining solution is cooled to 0 ° C. and cooled by dropwise addition of methanol. After evaporation of the solvent, the residue is dissolved in methylene chloride / methanol / acetone. Purification of this residue was carried out using silica gel chromatography, eluting with a solvent gradient of 1-5% methanol / methylene chloride, to give 4-chloro-7-hydroxy-6-methoxy-quinoline-3-carbonitrile. 0.075 g is provided as a yellow solid, decomposition> 245 ° C .; Mass spectrum (electrospray, m / e) M + H 235.2.

Example 37

4-Chloro-6-methoxy-7- (3-pyridin-4-yl-propoxy) -quinoline-3-carbonitrile

0.070 g of 4-chloro-7-hydroxy-6-methoxy-quinoline-3-carbonitrile, 0.062 g of 3- (4-pyridyl) -1-propanol and 0.235 g of triphenylphosphine in 3 ml of methylene chloride The mixture is cooled to 0 ° C. under nitrogen. 0.14 ml of diethyl azodicarboxylate is added dropwise thereto. After 30 minutes, the reaction mixture is allowed to warm to room temperature and stirred for a further 2 hours. The mixture was concentrated to 1 mL and purified by silica gel chromatography eluting with a solvent gradient of 1 to 2% methanol / methylene chloride to give 4-chloro-6-methoxy-7- (3-pyridin-4-yl-pro 0.090 g of foxy) -quinoline-3-carbonitrile is obtained as off-white rubber.

Example 38

4-chloro-7-methoxy-quinoline-3-carbonitrile

A mixture of 4.0 g (20 mmol) of 1,4-dihydro-7-methoxy-4-oxo-quinoline-3-carbonitrile and 8.3 g (40 mmol) of phosphorus pentachloride is heated at 165 ° C. for 3 hours. . Dilute the mixture with hexanes and collect the solids. The solid is mixed with brine, diluted with sodium hydroxide solution and extracted several times with a mixture of tetrahydrofuran and ethyl acetate. The solution was dried over magnesium sulphate and filtered through a pad of silica gel to give 3.7 g of 4-chloro-7-methoxy-quinoline-3-carbonitrile as a white solid: mass spectrum (electrospray, m / e): M + H 218.9.

Example 39

3-carethoxy-4-hydroxy-6,7-dimethoxyquinoline

A mixture of 30.6 g of 4-aminoveratrol and 43.2 g of diethyl ethoxymethylenemalonate is heated at 100 ° C. for 2 hours and at 165 ° C. for 0.75 hours. The intermediate so obtained is dissolved in 600 ml of diphenyl ether and the resulting solution is heated at reflux for 2 hours, cooled and then diluted with hexane. The resulting solid is filtered, washed with hexanes and then ether and dried to give the title compound as a brown solid, mp 275-285 ° C.

Example 40

3-carethoxy-4-chloro-6,7-dimethoxylquinoline

A mixture of 28.8 g of 3-carbethoxy-4-hydroxy-6,7-dimethoxyquinoline and 16.6 ml of phosphorus oxychloride was stirred at 110 ° C. for 30 minutes, cooled to 0 ° C. and then iced and ammonium hydroxide Treat with a mixture of side. The resulting gray solid is filtered off, washed with water and ether and then dried, mp 147-150 ° C.

Example 41

Ethyl 2-cyano-3- (3,4-dimethoxyphenylamino) acrylate

A mixture of 7.66 g of 4-aminoveratrol, 8.49 g of ethyl ethoxymethylenecyanoacetate and 20 ml of toluene is heated at 100 ° C. for 90 minutes. Toluene is evaporated to give a solid, mp 150-155 ° C.

Example 42

1,4-dihydro-6,7-dimethoxy-4-oxo-quinoline-3-carbonitrile

A mixture of 40 g of ethyl 2-cyano-3- (3,4-dimethoxyphenylamino) acrylate and 1.2 L of Dowtherm ^R A is refluxed for 10 hours, cooled and diluted with hexanes. The resulting solid is filtered off, washed with hexanes, then with dichloromethane and dried; mp 330-350 ° C. (decomposition).

Example 43

4-Chloro-6,7-dimethoxy-quinoline-3-carbonitrile

A stirred mixture of 20 g of 1,4-dihydro-6,7-dimethoxy-4-oxo-quinoline-3-carbonitrile and 87 ml of phosphorus oxychloride was refluxed for 2 hours, cooled and then free of volatiles To evaporate. The residue is stirred with dichloromethane-water at 0 ° C. while solid sodium carbonate is added until the aqueous layer is at pH 8. The organic layer is separated, washed with water, dried and concentrated. Recrystallization from dichloromethane gives a solid, mp 220-223 ° C.

Example 44

Methyl 2- (dimethylaminomethyleneamino) benzoate

To a stirred solution of 7.56 g of methyl anthranilate in 50 ml of dimethylformamide is added 5.6 ml of phosphorus oxychloride at 0 ° C. for 15 minutes. The mixture is heated at 55 ° C. for 45 minutes, cooled to 0 ° C. and diluted with dichloromethane. The mixture is basified by the slow addition of cold 1 N NaOH from 0 ° C. to pH 9. The dichloromethane layer is separated, washed with water, dried and concentrated to an oil.

Example 45

1,4-dihydro-4-oxo-quinoline-3-carbonitrile

A stirred mixture of 1.03 g of methyl 2- (dimethylaminomethyleneamino) benzoate, 0.54 g of sodium methoxide, 1.04 mL of acetonitrile and 10 mL of toluene is refluxed for 18 hours. The mixture is cooled, treated with water and brought to pH 3 by addition of dilute HCl. The resulting solid is extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is recrystallized from ethanol to give a solid, mp 290-300 ° C.

Example 46

4- (3-Chloro-propoxy) -5-methoxy-benzoic acid methyl ester

102.4 g (411.7 mmol) of 3-chloropropyl p-toluene sulfonate in 900 ml of acetone, 75 g (411.7 mmol) of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 75.7 g (547.5 mmol) of potassium carbonate and methyl A mixture of 1.66 g (4.1 mmol) of tricapryl ammonium chloride is stirred rapidly at reflux for 18 hours. The mixture is filtered and the solvent is removed to give 106 g of the title compound after recrystallization from the chloroform-hexane mixture.

Example 47

4- (2-Chloro-ethoxy) -5-methoxy-benzoic acid methyl ester

Using the same method as in Example 46, 77 g of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 99.2 g of 2-chloroethyl p-toluene sulfonate, 77.7 g of potassium carbonate and methyl-tricapryl ammonium chloride 1.7 g (4.1 mmol) are converted to 91.6 g of the title compound: mass spectrum (electrospray, m / e): M + H 245.0.

Example 48

4- (3-Chloro-propoxy) -5-methoxy-2-nitro-benzoic acid methyl ester

To a solution of 100 g (386.5 mmol) of 4- (3-chloro-propoxy) -5-methoxy-benzoic acid methyl ester in 300 ml of acetic acid is added dropwise 100 ml of 70% nitric acid. The mixture is heated to 50 ° C. for 1 hour and then poured into ice water. The mixture is extracted with chloroform. The organic solution is washed with dilute sodium hydroxide and then dried over magnesium sulphate. Remove the solvent. Ether is added and the mixture is stirred until a solid is deposited. The solid was collected by filtration to give 98 g of 4- (3-chloro-propoxy) -5-methoxy-2-nitro-benzoic acid methyl ester as white crystals: mass spectrum (electrospray, m / e): M + H 303.8; 2M + NH ₄ 623.9.

Example 49

4- (2-Chloro-ethoxy) -5-methoxy-2-nitro-benzoic acid methyl ester

Using the same method as in Example 48, nitriding 85 g of 4- (2-chloro-ethoxy) -5-methoxy-benzoic acid methyl ester gave 72 g of the title compound: mass spectrum (electrospray, m / e): 2M + NH ₄ 595.89.

Example 50

2-Amino-4- (3-chloro-propoxy) -5-methoxy-benzoic acid methyl ester

A mixture of 91 g (299.6 mmol) of 4- (3-chloro-propoxy) -5-methoxy-2-nitro-benzoic acid methyl ester with 55.2 g (988.8 mmol) of iron was added with 60.1 g of ammonium chloride, 500 ml of water, and methanol. Mechanically stirred at reflux for 5.5 hours in a mixture containing 1300 ml. The mixture is concentrated and mixed with ethyl acetate. The organic solution is washed with water and saturated sodium bicarbonate. The solution is dried over magnesium sulphate and filtered through a short column of silica gel. The solvent is removed and the residue is mixed with 300 mL of ether-hexane 2: 1. After standing 73.9 g of the title compound are obtained as a pink solid: mass spectrum (electrospray, m / e): 2M-HCl + H 511.0; M + H 273.8.

Example 51

2-Amino-4- (2-chloro-ethoxy) -5-methoxy-benzoic acid methyl ester

A mixture of 68.2 g (235.4 mmol) of 4- (2-chloro-ethoxy) -5-methoxy-2-nitro-benzoic acid methyl ester with 52.6 g (941.8 mmol) of iron was refluxed at 62.9 g of ammonium chloride and 393 mL of water. And mechanically stirred for 15 hours in a mixture containing 1021 ml of methanol. The mixture is concentrated and mixed with ethyl acetate. The organic solution is washed with water and saturated sodium bicarbonate. The solution is dried over magnesium sulphate and filtered through a short column of silica gel. The solution is concentrated to 200 mL and diluted with hot hexane 250. After standing, 47.7 g of the title compound are obtained as a solid: mass spectrum (electrospray, m / e) M + H 259.8.

Example 52

7- (2-chloro-ethoxy) -4-hydroxy-6-methoxy-quinoline-3-carbonitrile

A mixture of 25 g (96.3 mmol) of 2-amino-4- (2-chloro-ethoxy) -5-methoxy-benzoic acid methyl ester and 17.2 g (144.4 mmol) of dimethylformamide dimethylacetal was heated to reflux for 1.5 hours. do. Excess reagent is removed under reduced pressure leaving 30.3 g of residue and dissolved in 350 ml of tetrahydrofuran. In a separate flask, 8.3 g (202.1 mmol) of acetonitrile were added dropwise at -78 ° C over 40 minutes to 80.9 ml of a 2.5 M n-butyl lithium stirred solution of hexane in 300 ml tetrahydrofuran. After 30 minutes, the solution of amidine is added dropwise at -78 ° C over 45 minutes. After 1 hour 27.5 ml of acetic acid are added and the mixture is allowed to warm to room temperature. Remove the solvent and add water. The solid is collected by filtration and washed with water and ether. After drying in vacuo, 18.5 g of the title compound are obtained as a tan powder: mass spectrum (electrospray, m / e) M + H 278.8.

Example 53

7- (3-chloro-propoxy) -4-hydroxy-6-methoxy-quinoline-3-carbonitrile

Using the method of Example 52 starting from the corresponding amidine 6.01 g, acetonitrile 1.58 g and 15.35 mL of n-butyl lithium solution, 3.7 g of the title compound are obtained as a tan powder: mass spectrum (electrospray, m / e) M + H 292.8; 2M + H 584.2.

Example 54

7- (3-chloro-propoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile

A mixture of 3.5 g (12 mmol) of 7- (3-chloro-propoxy) -4-hydroxy-6-methoxy-quinoline-3-carbonitrile and 28 ml of phosphorus oxychloride was refluxed for 1.5 h. Excess reagent is removed at reduced pressure. The residue is mixed with ice cold dilute sodium hydroxide and ethyl acetate. The mixture is extracted with a combination of ethyl acetate and tetrahydrofuran. The combined extracts are washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate and filtered through a single column of silica gel. Removal of the solvent affords 3.2 g of the title compound as a pink solid, which is further purified and used.

Example 55

7- (2-chloro-ethoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile

8 g (28.7 mmol) of 7- (2-chloro-ethoxy) -4-hydroxy-6-methoxy-quinoline-3-carbonitrile and oxalyl chloride in 80 ml of methylene chloride containing 0.26 g of dimethylformamide 18.2 g (143.5 mmol) of solution are stirred at reflux for 2.5 h. Remove the solvent. The residue is mixed with dilute cold sodium hydroxide and extracted several times with ethyl acetate and tetrahydrofuran. The combined extracts are dried over magnesium sulphate and the solution is passed through a single column of silica gel. The solvent is removed to give 6.0 g of the title compound as off white solid which is used without further purification.

Example 56

4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile

A mixture of 7.95 g (32.6 mmol) of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile and 50 ml of phosphorus oxychloride was refluxed for 3 hours 40 minutes. Phosphorus oxychloride is removed in vacuo and the residue is slurried with ice water. Solid NaHCO ₃ is added (pH 8) and the product is collected by filtration, washed well with water and dried in vacuo (40 ° C.). The amount of fresh shank is 7.75 g of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile as a tan solid: Mass spectrum (electrospray, m / e): M + H 262.8, 264.8.

Example 57

6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile

A solution of 10.2 g (45.3 mmol) of methyl 2-amino-5-ethoxy-4-methoxy benzoate and 10.8 g (90.7 mmol) of dimethylformamide dimethyl acetal in 50 ml of dimethylformamide is refluxed for 3 hours. The volatiles are removed and the residue is boiled with toluene and dried in vacuo to yield formamidine as a purple syrup. N-butyllithium (100 mmol) in hexane is diluted with 60 mL of tetrahydrofuran at -78 ° C. A solution of 4.18 g (102 mmol) of acetonitrile in 80 ml of tetrahydrofuran is added over 15 minutes and the solution is stirred for 20 minutes. Crude formamidine is dissolved in 80 ml of tetrahydrofuran and added dropwise to the cold solution over 0.5 hour. After stirring for 2 hours, the reaction mixture is cooled to 13 ml of acetic acid at -78 ° C. It is warmed to room temperature and the volatiles are removed in vacuo. The residue is slurried with water and the crude product is collected by filtration, washed with water and dried. The material is then washed with chloroform and dried to give 7.95 g of 6-ethoxy-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile as yellow crystals: mass spectrum (electrospray) , m / e): MH 243.2.

Example 58

Methyl 2-amino-5-ethoxy-4-methoxybenzoate

A mixture of 17.0 g (66.7 mmol) of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate, 13.1 g (233 mmol) of powdered iron and 17.7 g (334 mmol) of ammonium chloride in 95 ml of water and 245 ml of methanol Reflux for 4.5 hours. An additional 13.1 g of iron is added and then refluxed for 2.5 hours. Further 13.1 g of iron and 17.7 g of ammonium chloride are added and refluxing is continued for 12 hours. The reaction mixture is filtered through celite and methanol is removed from the filtrate. The filtrate is extracted with chloroform and the extract is treated with Darco, evaporated and dried in vacuo (50 ° C.). The yield is tan crystals, 11.0 g of methyl 2-amino-5-ethoxy-4-methoxybenzoate: mass spectrum (electrospray, m / e): M + H 225.9.

Example 59

Methyl 5-ethoxy-4-methoxy-2-nitrobenzoate

A mixture of 15.0 g (74.1 mmol) of methyl 3-ethoxy-4-methoxybenzoate in 45 ml of acetic acid is treated dropwise with 15 ml of concentrated nitric acid over 12 minutes. The reaction mixture is held at 55 ° C. for 45 minutes, cooled to 25 ° C. and then poured into ice water. The product is extracted with methylene chloride and the extract is washed with water and dilute sodium hydroxide, dried and evaporated. The yield is yellow crystals, 17.8 g of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate: mass spectrum (electrospray, m / e): M + H 256.0.

Example 60

Methyl 3-ethoxy-4-methoxybenzoate

A mixture of 24.3 g (134 mmol) of methyl 3-hydroxy-4-methoxybenzoate, 36.8 g (267 mmol) of anhydrous potassium carbonate and 31.4 g (201 mmol) of ethyl iodine in 500 ml of dimethylformamide was 5.5 at 100 ° C. Stir for hours. Additional amounts of ethyl iodine (31.4 g) and potassium carbonate (18.4 g) are added and heating is continued for another 2 hours. The reaction mixture is filtered and volatiles are removed from the filtrate in vacuo. The residue is slurried with water and filtered to collect the product, which is washed with water and dried. Recrystallization from heptane affords 15.6 g of methyl 3-ethoxy-4-methoxybenzoate as white crystals: mass spectrum (electrospray, m / e): M + H 210.9.

Example 61

Methyl 3-hydroxy-4-methoxybenzoate

A solution of 30.8 g (183 mmol) of 3-hydroxy-4-methoxybenzoic acid and 6 ml of concentrated sulfuric acid in 600 ml of methanol was refluxed overnight. Most of the solvent is removed and the residual solution is poured into 600 ml of water containing 25 g of sodium bicarbonate. The product is extracted with ether, treated with Darco, dried and evaporated. The yield is 31.8 g of methyl 3-hydroxy-4-methoxybenzoate as light yellow crystals.

Example 62

N '-[2-carethoxy-4,5-bis (2-methoxyethoxy) phenyl] -N, N-dimethylformamidine

Phosphorus oxychloride (5.6 mL, 60 mmol) in a stirred solution of 15.7 g (50 mmol) (WO-96130347) of ethyl 2-amino-4,5-bis (2-methoxyethoxy) benzoate in 50 mL of DMF. Is added at 0 ° C. for 15 minutes. The resulting solution is heated at 55 ° C. for 45 minutes, cooled, diluted with methylene chloride and then treated with 200 ml of N / 1 sodium hydroxide at 0 ° C. for 2 minutes. The organic layer is separated and washed with water at 0 ° C. The solution is dried, evaporated and toluene is added to give 18.4 g of amber oil; NMR (CDCl ₃ ) δ 3.02 (s, Me ₂ N).

Example 63

1,4-dihydroquinoline-5,6-bis (2-methoxyethoxy) -3-carbonitrile

To a stirred solution of n-butyllithium (2.5 M 44 mL in hexanes; 110 mmol) in 65 mL of THF is added a solution of acetonitrile (5.85 mL, 112 mmol) in 110 mL of THF for 10 minutes at -78 ° C. After stirring at −78 ° C. for 15 minutes, the mixture was stirred in 75 ml of THF with N ′-[2-carethoxy-4,5-bis (2-methoxyethoxy) phenyl] -N, N-dimethylformami Treat with a solution of Dean for 20 minutes. After 30 min at −78 ° C. the stirred mixture is treated with acetic acid (14.3 mL, 250 mmol). The mixture is warmed to 25 ° C. and stirred for 2 hours. The mixture is evaporated to dryness and diluted with water. The resulting white solid is filtered, washed with water and dried to give 10.7 g; Mass spectrum (electrospray, m / e) M + H 319.2.

Example 64

4-Chloro-5,6-bis (2-methoxyethoxy) -quinoline-3-carbonitrile

A stirred mixture of 1,4-dihydroquinoline-5,6-bis (2-methoxyethoxy) -3-carbonitrile (9.68 g, 30.4 mmol) and 30 ml of phosphorus oxychloride was refluxed for 1.5 h. The resulting solution is concentrated in vacuo and the residue is stirred with methylene chloride at 0 ° C. while ice water and sodium carbonate are added until the pH of the mixture is 8-9. The organic layer is separated, washed with water, dried and concentrated to give a tan solid; Mass spectrum (electrospray, m / e) M + H 337.1, 339.1.

Example 65

Methyl 4-methoxy-3- (3-morpholin-4-yl-propoxy) benzoate

Methyl isovanylate (22.6 g, 124 mmol), N- (3-chloropropyl) -morpholine (25.4 g, 155 mmol), potassium carbonate (18.8 g, 136 mmol), tetrabutylammonium iodine (0.92 g, 2.5 mmol) and 248 mL of 2-butanone are refluxed for 20 hours. 2-butanone is evaporated and the residue is stirred at 0 ° C. with water. The resulting white solid is filtered off, washed successively with water and hexanes and then dried; mp 90-94 ° C.

Example 66

Methyl 4-methoxy-5- (3-morpholin-4-yl-propoxy) -2-nitrobenzoate

To a stirred solution of methyl 4-methoxy-3- (3-morpholin-4-yl-propoxy) benzoate (30.9 g, 100 mmol) in 100 ml of acetic acid was added 50 ml of 70% nitric acid at 25 ° C. for 30 minutes. Add. The solution is heated to 45 ° C. and the reaction starts at this temperature and self-suspends at this temperature. After a total of 1.5 hours at 45-50 ° C. the mixture is cooled to 0 ° C., treated with ice water and 240 g (1.75 mol) of potassium carbonate and then extracted with ethyl acetate. The extract is washed with water, dried and concentrated to give a yellow solid, mp 78-82 ° C.

Example 67

Methyl 2-amino-4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate

A solution of methyl 4-methoxy-3- (3-morpholin-4-yl-propoxy) -2-nitrobenzoate (32.5 g, 91.7 mmol) in 110 mL methanol and 220 mL ethyl acetate was added 10% on carbon. Hydrogenated at 25 ° C., 55 psi in the presence of Pd 2.0 g catalyst. After 4 hours the mixture is filtered and the filtrate is evaporated to dryness. The residue is recrystallized from acetone-hexane to give a tan solid, mp 78-82 ° C.

Example 68

Ethyl 2- (dimethylaminomethyleneamino) -4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate

A mixture of 2-amino-4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate (6.49 g, 20 mmol) and dimethylformamide dimethyl acetal (4.25 mL, 30 mmol) was prepared in 100 Heat 1.5 ° C. All volatiles were evaporated directly at 70 ° C. to obtain a syrup; Mass spectrum (electrospray, m / e) M + H 380.5.

Example 69

1,4-dihydroquinolin-7-methoxy-6- (3-morpholin-4-yl-propoxy) -4-oxo-3-carbonitrile

To a stirred solution of n-butyllithium (2.5 M 17.6 mL in hexanes; 44 mmol) in 26 mL THF is added a solution of acetonitrile (1.85 mL, 45 mmol) in 44 mL THF for 10 min at -78 ° C. After stirring at −78 ° C. for 15 minutes, the mixture was diluted with ethyl 2- (dimethylaminomethyleneamino) -4-methoxy-5- (3-morpholin-4-yl-propoxy) benzoate in 30 mL THF. 7.6 g, 20 mmol) for 20 minutes. After 90 minutes at −78 ° C. the mixture is slowly warmed to 25 ° C. with carbon dioxide treatment and then evaporated to dryness. The residue is partitioned between n-butanol (200 mL) and semi-saturated NaCl solution (40 mL). The organic layer is separated, washed with saturated NaCl solution and evaporated to dryness. The resulting solid was successively ground with boiling acetone and methanol, filtered and dried to give a tan solid, mp 255-260 ° C.

Example 70

4-Chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile

1,4-dihydroquinolin-7-methoxy-6- (3-morpholin-4-yl-propoxy) -4-oxo-3-carbonitrile (4.75 g, 13.8 mmol), DMF 0.10 mL and tee A stirred mixture of 55 ml of onyl chloride is refluxed for 3 hours. The volatiles are removed by evaporation at 30 ° C. and the residue is stirred at 0 ° C. with a mixture of methylene chloride containing potassium carbonate and water to give a pH 9-10. The organic layer is separated, washed with water, dried and concentrated to give a brown solid; Mass spectrum (electrospray, m / e) M + H 362.4, 364.4.

Example 71

4-Chloro-7-ethoxy-6-methoxy-quinoline-3-carbonitrile

122 mg (0.50 mmol) of 7-ethoxy-1,4-dihydro-6-methoxy-4-oxo-quinoline-3-carbonitrile and 2.0 ml of methylene chloride were mixed under N ₂ and at a temperature near 25 ° C. Keep it. 218 μl (2.5 mmol) of oxalyl chloride and 10 μl (0.125 mmol) of DMF are added. Stir overnight, dilute with chloroform and stir until saturated in saturated sodium bicarbonate. The layers were separated and the organics were dried over magnesium sulfate, the solvent was stripped and dried in vacuo to give 117 mg of a tan solid: mass spectrum (electrospray m / e): M + H = 262.8, 264.8.

Example 72

7-ethoxy-1,4-dihydro-6-methoxy-4-oxo-quinoline-3-carbonitrile

54.0 mL (135 mmol) of n-butyl lithium are added to 150 mL of THF and cooled under N ₂ to −78 ° C. 7.05 mL (135 mmol) of acetonitrile in 200 mL of THF is added dropwise over 20 minutes. Stir for 15 minutes and add a solution of 17.99 g (64.2 mmol) of methyl 4-ethoxy-5-methoxy-2- (dimethylaminomethyleneamino) benzoate in 150 ml THF dropwise in 20 minutes. Stir at −78 ° C. for 0.5 h. 11.0 mL (193 mmol) of acetic acid are added and slowly warmed to 25 ° C. After 2.5 hours, the solvent is stripped, the residue is slurried with water, the solids are collected and dried in vacuo to give 13.025 g of a yellow solid: mass spectrum (electrospray m / e): M + H = 245.2 .

Example 73

Methyl 4-ethoxy-5-methoxy-2- (dimethylaminomethyleneamino) benzoate

A mixture of 15.056 g (66.9 mmol) of methyl 2-amino-4-ethoxy-5-methoxybenzoate and 14.1 mL (100 mmol) of N, N-dimethylformamide dimethylacetal is heated to 100 ° C. under N ₂ . Add 4.7 ml (33.3 mmol) of DMF / DMA at 4.5 hours and remove heat at 5 hours. The solvent is stripped, boiled with toluene and dried in vacuo to give 18.211 g of an off-brown solid: mass spectrum (electrospray m / e): M + H = 281.3.

Example 74

Methyl 2-amino-4-ethoxy-5-methoxybenzoate

A mixture of 24.110 g (94.5 mmol) methyl 4-ethoxy-5-methoxy-2-nitrobenzoate, 15.81 g (283 mmol) iron powder, 25.28 g (472 mmol) ammonium chloride, 135 ml water and 350 ml methanol Is heated to reflux under N ₂ . Equal amounts of iron and ammonium chloride are added at both 3 and 5.5 hours. Heat is removed at 6.5 hours, ethyl acetate and saturated sodium bicarbonate are added, filtered through celite and the layers are separated. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, the solvent was stripped and then dried in vacuo to give 17.594 g of a pink solid: mass spectr (electrospray m / e): M + H = 226.2.

Example 75

Methyl 4-ethoxy-5-methoxy-2-nitrobenzoate

5.00 g (23.7 mmol) of methyl 4-ethoxy-3-methoxybenzoate are dissolved in 25 mL of acetic acid under N ₂ and 6.1 mL (95.1 mmol) of 69% nitric acid is added dropwise over 30 minutes. Heat to 50 ° C. for 1.5 h and pour into ice bath. Extract with chloroform, wash with dilute sodium hydroxide solution and filter through magnesium sulfate. Strip the solvent and dry in vacuo to give 5.268 g of an off-white solid: mass spectrum (electrospray m / e): M + H = 255.8.

Example 76

Methyl 4-ethoxy-3-methoxybenzoate

A mixture of 25.0 g (137 mmol) methyl vanylate, 38.87 g (274 mmol) potassium carbonate, 500 mL DMF and 16.5 mL (206 mmol) ethyl iodine is heated to 100 ° C. under N ₂ . At 2.5 hours, cool and remove solids. Strip the solvent and fractionate water and methylene chloride. Strip the solvent and dry in vacuo to give 25.85 g of a white solid: mass spectrum (EI m / e): M = 210.0.

Example 77

7-ethoxy-4-hydroxy-quinoline-3-carbonitrile

A mixture of 10 g (73 mmol) of 3-ethoxy aniline and 12.3 g (73 mmol) of ethyl (ethoxymethylene) cyanoacetate is heated at 90 ml of Dowther, 140 ° C. for 7 hours. To the mixture is added 250 ml of Dowther. The solution is stirred and periodically distilled to reflux for 12 hours under nitrogen while removing ethanol. The mixture is cooled to room temperature, the solids collected and washed with hexanes. The crude solid was treated with boiling ethanol and then filtered to give 9.86 g of a brown solid: mass spectrum (electrospray, m / e): M + H 214.7.

Example 78

7-ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile

To a suspension of 5 g (23 mmol) of 7-ethoxy-4-hydroxy-quinoline-3-carbonitrile in 75 ml of trifluoroacetic anhydride, 5.5 g (69 mmol) of ammonium nitrate were added over 6 hours at room temperature do. Excess anhydride is removed at 45 ° C. under reduced pressure. The residue is stirred with 300 ml of water. The solids were collected and treated with boiling ethanol to yield 3.68 g of tin solids: mass spectrum (electrospray, m / e) M + H 259.8.

Example 79

4-chloro-7-ethoxy-6-nitro-quinoline-3-carbonitrile

A mixture of 3.45 g (13 mmol) of 7-ethoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 5.55 g (26 mmol) of phosphorus pentachloride and 10 ml of phosphorus oxychloride was added for 3 hours. Reflux. Dilute the mixture with hexanes and collect the solids. The solid is dissolved in 500 ml of ethyl acetate and washed with dilute cold sodium hydroxide solution. The solution is dried over magnesium sulphate and filtered through a pad of silica gel. Remove the solvent to afford 2.1 g of beige solid: mass spectrum (electrospray, m / e) M + H 277.7.

Example 80

8-methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile

A mixture of 12.6 g (75 mmol) of 2-methoxy-4-nitroaniline and 12.7 g (75 mmol) of ethyl (ethoxymethylene) cyanoacetate was heated in 100 ml of Dowther, overnight at 120 ° C. and 20 ° C. for 20 hours. do. 300 ml of Dowther is added to this mixture. The solution is stirred and periodically distilled to reflux for 12 hours under nitrogen while removing ethanol. The mixture is cooled to room temperature, the solids collected and washed with hexanes. The crude solid was treated with boiling ethanol and then filtered to give 12 g of a brown solid: mass spectrum (electrospray, m / e): M + H 245.8.

Example 81

4-chloro-8-methoxy-6-nitro-quinoline-3-carbonitrile

A mixture of 4 g (16 mmol) of 8-methoxy-4-hydroxy-6-nitro-quinoline-3-carbonitrile, 6.66 g (32 mmol) of phosphorus pentachloride and 15 mL of phosphorus oxychloride was added for 2.5 hours. Reflux. Dilute the mixture with hexanes and collect the solids. The solid is dissolved in 500 ml of ethyl acetate and washed with dilute cold sodium hydroxide solution. The solution is dried over magnesium sulphate and filtered through a pad of silica gel. Remove the solvent to afford 2.05 g of a tan solid: mass spectrum (electrospray, m / e) M + H 263.7.

Example 82

4-hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile

A mixture of 4.82 g of methyl 3,4,5-trimethoxyanthranilate in 20 ml of N.N-dimethylformamide dimethyl acetal is refluxed for 18 hours and concentrated in vacuo. Amidine crude is used in the next step without further purification.

To 25 mL of tetrahydrofuran 17.6 mL of 2.5 M n-butyllithium in hexane are added at -78 ° C. Then 2.35 ml of acetonitrile in 45 ml of tetrahydrofuran are added dropwise. The mixture is stirred at -78 ° C for 15 minutes. Then a solution of crude amidine in 30 ml of tetrahydrofuran is added dropwise. The mixture is stirred for 30 min at -78 &lt; 0 &gt; C, then 5.7 ml of acetic acid are added. The mixture is allowed to warm to room temperature and 100 ml of water are added. The product was collected, washed with water and dried to give 4.14 g of 4-hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 280 ° C. (decomposition); Mass spectrum (electrospray, m / e): M + H 261.2.

Example 83

4-Chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile

A stirred mixture of 1.30 g of 4-hydroxy-6,7,8-trimethoxy-quinoline-3-carbonitrile, 10 ml of phosphorus oxychloride and 1 drop of N, N-dimethylformamide was refluxed for 10 minutes and volatile Evaporate to avoid material. The residue is stirred with 20 ml of 5% methyl alcohol in ethyl acetate. The product was collected and dried to give 1.12 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 161-163 ° C .; Mass spectrum (EI, m / e): M 278.0452.

Example 84

2- (dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methyl ester

2-amino-3,6-dimethoxybenzoic acid in 20 ml of N, N-dimethylformamide dimethyl acetal (Manouchehr Azadi-Ardakani and Timothy W. Wallace, Tetrahedron, Vol. 44, No. 18, pp. 5939 to 5952, 1988) 3.46 g of the mixture is refluxed for 18 hours and concentrated in vacuo. To the residue is added 180 ml of ethyl acetate. The mixture is filtered and 200 ml of hexane is added to the filtrate. The mixture is then concentrated to 100 ml. The product was collected and dried to give 3.25 g of 2- (dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methylester as a solid, mp 81-83 ° C .; Mass spectrum (EI, m / e): M 266.1263.

Example 85

4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile

To 12.5 mL of tetrahydrofuran is added 8.8 mL of 2.5 M n-butyllithium in hexanes at -78 ° C. Then 1.18 ml of acetonitrile in 25 ml of tetrahydrofuran are added dropwise. The mixture is stirred at -78 ° C for 15 minutes. Then a solution of 2- (dimethylamino-methyleneamino) -3,6-dimethoxy-benzoic acid methylester in 62 ml of tetrahydrofuran is added dropwise. The mixture is stirred at −78 ° C. for 10 minutes and then warmed to room temperature for 15 minutes. Acetic acid (3 mL) is added followed by 200 mL of water. The product was collected, washed with water and dried to yield 1.57 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 300-305 ° C .; Mass spectrum (EI, m / e): M 230.0685.

Example 86

4-chloro-5,8-dimethoxy-quinoline-3-carbonitrile

A stirring mixture of 1.30 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile, 10 ml of phosphorus oxychloride and 2 drops of N, N-dimethylformamide was refluxed for 10 minutes and volatile free To evaporate. The residue is stirred with 50 ml of water. The product was collected and dried to give 1.74 g of 4-chloro-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 165-167 ° C .; Mass spectrum (EI, m / e): M 248.0346.

Example 87

Methyl 2- (dimethylaminomethyleneamino) -4,5-diethoxybenzoate

To a stirred solution of methyl 2-amino-4,5-diethoxybenzoate (4.79 g, 20 mmol) in 20 mL DMF is added phosphorus oxychloride (2.24 mL, 24 mmol) at 0 ° C. for 15 minutes. The mixture is warmed to 55 ° C. and stirred for 45 minutes. The resulting solution is diluted with methylene chloride, cooled to 0 ° C. and treated with 80 ml of precooled N / 1 sodium hydroxide for 5 minutes. The organic layer is separated and washed with water at 0 ° C. The solution is dried and concentrated to give an amber oil; NMR (CDCl ₃ ) δ 3.00 (s, Me ₂ N).

Example 88

1,4-dihydroquinoline-6,7-diethoxy-4-oxo-3-carbonitrile

To a stirred solution of n-butyllithium (2.5 M 17.6 ml in hexanes; 44 mmol) in 25 ml THF is added a solution of acetonitrile (2.35 ml, 45 mmol) in 44 ml THF for 10 minutes. After stirring at −78 ° C. for 15 minutes, the mixture is treated with a solution of ethyl 2- (dimethylaminomethyleneamino) -4,5-diethoxybenzoate (5.83 g, 19.8 mmol) in 30 ml of THF for 30 minutes. . After 30 min at −78 ° C. the mixture is treated with 5.7 mL (100 mmol) of acetic acid and evaporated to dryness. The residue is stirred in water, the resulting precipitate is filtered off, washed with water and dried to give 4.01 g of an off-white solid; NMR (DMSO-d ₆ ) d 8.58 (s, 2-H).

Example 89

4-Chloro-6,7-diethoxy-quinoline-3-carbonitrile

Treatment of 1,4-dihydroquinoline-6,7-diethoxy-4-oxo-3-carbonitrile with phosphorus oxychloride in the method of Example 64 yields the title compound as a pink solid, mp 170-. 175 ° C.

Example 90

2- (dimethylamino-methyleneamino) -3-methoxy-benzoic acid methyl ester

The reaction mixture of 5.0 g (29.9 mmol) of 2-amino-3-methoxy-benzoic acid in 25.0 ml of DMF-DMA is heated at 100-105 ° C. for 2.5 hours, then the solvent is removed to give a red-purple viscous oil. . After standing in the refrigerator, the oil solidifies to yield 5.8 g of the product as a red-purple solid in 82.8% yield, mass spectrum (electrospray, m / e): M + H 236.9.

Example 91

1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carbonitrile

To 35.0 mL THF, 26.6 mL (66.4 mmol) of n-BuLi solution are added at -78 ° C for 5 minutes. To the stirred solution is added a solution of 3.55 mL (67.9 mmol) CH ₃ CN in 65 mL THF for 10 minutes, at which time the solution becomes a white suspension and stirring is continued at −78 ° C. for 15 minutes. To the suspension was added a solution of 5.8 g (24.5 mmol) of 2- (dimethylamino-methyleneamino) -3-methoxy-benzoic acid methyl ester in 45 mL of THF for 30 minutes, followed by continued stirring at -78 ° C for 30 minutes At this time the mixture gradually becomes transparent. The solution is cooled to 8.5 ml HOAc. The resulting turbid slurry is stirred and warmed to room temperature. After most of the solvent has evaporated, the residue is diluted with cold water. The separated solids are collected by filtration and washed with water. After drying in vacuo, it yields 3.8 g of product as an off-white solid in 77.6% yield, mp 270 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 201.1.

Example 92

4-chloro-8-methoxy-quinoline-3-carbonitrile

A mixture of 3.8 g (19 mmol) of 1,4-dihydro-8-methoxy-4-oxo-quinoline-3-carbonitrile, 40 ml of phosphorus oxychloride and 5 drops of DMF was refluxed for 0.5 h. The mixture is evaporated to dryness and diluted with hexanes. The solids are collected, mixed with dilute cold sodium carbonate solution and extracted several times with ethyl acetate. The organic layer is dried over sodium sulphate and filtered through a pad of silica gel. Removal of the solvent yields 3.8 g of 4-chloro-8-methoxy-quinoline-3-carbonitrile as an off-white solid in 91% yield, mass spectrum (Electrospray, m / e): M + H 219.1.

Example 93

4-chloro-7-methoxy-quinoline-3-carbonitrile

Treatment of 1,4-dihydroquinoline-7-methoxy-4-oxo-3-carbonitrile with phosphorus oxychloride in the method of Example 64 yields the title compound as a tan solid; Mass spectrum (electrospray, m / e) M + H 219.2, 221.2.

Example 94

7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile

To a stirred solution of 26.9 ml of n-butyllithium (2.5 M in hexane) in 50 ml of THF, 3.51 ml of acetonitrile in 20 ml of THF are added at −78 ° C. for 10 minutes. After stirring at −78 ° C. for 30 minutes, the mixture is treated with 10 g of L17741-150 (B. Floyd) in 20 ml of THF for 5 minutes. After 15 minutes at −78 ° C. the stirred mixture is further warmed to 0 ° C. for 30 minutes. Then treat with 5 ml of acetic acid, warm to 25 ° C. and stir for 30 minutes. The mixture is evaporated to dryness and diluted with aqueous sodium bicarbonate. The resulting off-white solid is filtered off and washed with water, ethyl acetate and ether. After drying, 4.5 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile are obtained as an off-white solid, decomposition> 255 ° C .; Mass spectrum (electrospray, m / e) M + H 307.

Example 95

7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile

5 ml of oxalyl chloride (2 M in methylene chloride) and N, N-dimethyl in a stirred suspension of 1 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile in 10 ml of methylene chloride Add 2 drops of formamide. The mixture is refluxed for 20 minutes and aqueous sodium bicarbonate is added slowly thereto until bubbling stops. After separation of the layers, the organic layer is evaporated in small volumes and then passed through a plug of magnesol. Elution with 50 ml of methylene chloride and then evaporation gave 0.6 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as a pale yellow solid, mp 282-284 ° C .; Mass spectrum (electrospray, m / e) M + H 325.

Example 96

4- (2,3-Dihydro-1H-indol-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

A solution of 400 mg (1.44 mM) of 6-aminoindolin dihydrochloride salt and 258 mg (1.88 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 10 ml of ethanol was refluxed for 3 hours. Let's do it. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solids are collected, washed with water, then ether and dried at 80 ° C. under vacuum. The solid was dissolved in 50/50 methanol / chloroform, dried over silica gel and purified by chromatography using a gradient of 20% to 50% acetone in hexane to give 496 mg of the title compound as a tan solid: mass spectrum (electro Spray, m / e): M + H 375.1, mp = 121-124 ° C.

Example 97

4- (benzothiazol-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile HCl salt

A solution of 500 mg (1.8 mM) and 353 mg (2.35 mM) of 6-aminobenzothiazole in 15 mL of ethanol was refluxed for 3 hours. Two drops of concentrated HCl are added to the warm solution and the sample is heated at 100 ° C. for 5 minutes, then the solids are separated by filtration. The solid is taken up in 20 ml of ethanol and digested for 1 hour. The hot solution was filtered and the separated solid was washed with ethanol and dried at 80 ° C. under vacuum to afford 4- (benzothiazol-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile HCl salt 666 mg is obtained as a tan solid: mass spectrum (electrospray, m / e): M + H 391.0, mp = 285-287 ° C.

Example 98

4- (benzo [1,3] dioxol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

A solution of 400 mg (1.44 mM) and 3,4- (methylenedioxy) aniline 258 mg (1.88 mM) in 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 10 ml of ethanol was added for 3 hours. Reflux. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solids were collected, washed with water followed by ether and dried at 80 ° C. under vacuum to afford 4- (benzo [1,3] dioxol-5-ylamino) -6,7-diethoxy-quinoline-3-carbo 526 mg of nitrile are obtained as a tan solid: mass spectrum (electrospray, m / e): M + H 378.0, mp = 200-203 ° C.

Example 99

6,7-diethoxy-4- (1H-indazol-6-ylamino) -quinoline-3-carbonitrile

A solution of 400 mg (1.44 mM) and 6 mg-aminoindazole 250 mg (1.88 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 10 ml of ethanol was refluxed for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried at 80 ° C. in vacuo to give 448 mg of 6,7-diethoxy-4- (1H-indazol-6-ylamino) -quinoline-3-carbonitrile. Obtained as a tan solid: Mass spectrum (electrospray, m / e): M + H 374.1, mp = 143-145 ° C.

Example 100

6,7-diethoxy-4- (4-methyl-2-oxo-2H-chromen-7-ylamino) -quinoline-3-carbonitrile

A solution of 400 mg (1.44 mM) and 7-amino-4-methyl-coumarin 330 mg (1.88 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 15 ml of 2-methoxyethanol was added. Reflux for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water, then ether and dried at 80 ° C. under vacuum to give 6,7-diethoxy-4- (4-methyl-2-oxo-2H-chromen-7-ylamino) as a tan solid. 431 mg of quinoline-3-carbonitrile are obtained: mass spectrum (electrospray, m / e): M + H 416.0, mp = 282-284 ° C.

Example 101

6,7-diethoxy-4- (1H-indol-6-ylamino) -quinoline-3-carbonitrile

A solution of 964 mg (3.50 mM) and 6-aminoindole 830 mg (6.29 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 5 ml of 2-methoxyethanol was refluxed for 3 hours. . 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. Collected as a solid, washed with water followed by ether and dried at 80 ° C. in vacuo to give 712 mg of 6,7-diethoxy-4- (1H-indol-6-ylamino) -quinoline-3-carbonitrile yellow Obtained as a solid: mass spectrum (electrospray, m / e): M + H 373.0, mp = 128-130 ° C.

Example 102

6,7-dimethoxy-4- (1H-indazol-6-ylamino) -quinoline-3-carbonitrile

A solution of 500 mg (2.00 mM) of 6-aminoindazole and 975 mg (2.61 mM) of 6-aminoindazole in 15 ml of 2-methoxyethanol was refluxed for 3 hours. Let's do it. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solids were collected, washed with water, then ether and dried at 80 ° C. in vacuo to give 738 mg of the title compound as a tan solid: mass spectrum (electrospray, m / e): M + H 345.9, mp = 180 -183 ° C.

Example 103

4- (1H-Benzotriazol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

A solution of 1.07 mg (3.87 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 675 mg (5.00 mM) of 5-aminobenzotriazole in 15 ml of 2-methoxyethanol was added for 3 hours. Reflux. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solution is acetylated by addition of concentrated HCl and the solids are collected, washed with water, then ether and dried at 80 ° C. under vacuum. The solid is taken up in 200 mL methanol and 500 μL 5 N sodium hydroxide and boiled for 20 minutes. To this heterogeneous mixture is added 100 ml of glacial acetic acid and boiled to reduce the volume to a total of 100 ml. To a room temperature mixture, 500 ml of ice-cold water are added and the solids are collected, washed with water, then ether and dried at 80 ° C. in vacuo to give Name 738 mg as a brown solid: mass spectrum (electrospray, m / e): M + H 375.0, mp = 115 ° C. decomposition.

Example 104

4- (1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 305 mg (1.88 mM) of 4-aminophthalimide in 10 ml of ethanol was refluxed for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried at 80 ° C. under vacuum to afford 4- (1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino) -6, 348 mg of 7-diethoxy-quinoline-3-carbonitrile are obtained as a yellow solid: mass spectrum (electrospray, m / e): M + H402.9, mp = 248-251 ° C.

Example 105

4- (2,3-Dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

400 mg (1.44 mM) and 1,4-benzodioxane-6-amine 232 mg (1.54 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 15 ml of 2-methoxyethanol The solution is refluxed for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solids were collected, washed with water, then ether and dried at 80 ° C. under vacuum to afford 4- (2,3-dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-diethoxy 526 mg of -quinoline-3-carbonitrile are obtained as a yellow solid: mass spectrum (electrospray, m / e): M + H 402.9, mp = 225-227 ° C.

Example 106

4- (1H-indazol-6-ylamino) -6,7-bis- (2-methoxy-ethoxy) -quinoline-3-carbonitrile

Of 400 mg (1.19 mM) and 6-aminoindazole 174 mg (1.31 mM) of 4-chloro-6,7- (2-methoxyethoxy) -quinoline-3-carbonitrile in 12 ml of 2-methoxyethanol The solution is refluxed for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solid was collected, washed with water, then ether and dried at 80 ° C. under vacuum to afford 4- (1H-indazol-6-ylamino) -6,7-bis- (2-methoxy-ethoxy)- 362 mg of quinoline-3-carbonitrile are obtained as an orange solid: mass spectrum (electrospray, m / e): M + H 434.0, mp = 105-110 ° C.

Example 107

4- (1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 273 mg (1.54 mM) of 4-aminophthalhydrazide in 15 ml of 2-methoxyethanol was added. Reflux for time. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solution is acetylated by the addition of concentrated HCl and the solids collected, washed with water, then ether and dried at 80 ° C. under vacuum. The solid is taken up in 200 mL methanol and 500 μL 5 N sodium hydroxide and boiled for 20 minutes. To this heterogeneous mixture is added 100 ml of glacial acetic acid and boiled to reduce the volume to a total of 100 ml. To the room temperature mixture, 500 ml of ice cold water are added and the solid collected, washed with water, then ether and dried at 80 ° C. under vacuum. The solids are decomposed from 400 ml of ethanol until the volume is reduced to 150 ml. The hot solution was filtered and the solid was washed with ethanol and dried at 80 ° C. in vacuo to yield 121 mg of the title compound as a white solid: mass spectrum (electrospray, m / e): M + H 418.0, mp => 270 ℃.

Example 108

6,7-diethoxy-4- (indan-5-ylamino) -quinoline-3-carbonitrile

A solution of 400 mg (1.44 mM) and 5-205 indanane 205 mg (1.54 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 12 ml of 2-methoxyethanol was refluxed for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution, and the sample is heated at 100 ° C. for 5 minutes, and then poured into 300 ml of ice water. The solids are collected, washed with water, then ether and dried at 80 ° C. under vacuum. The brown solid is dissolved in 200 ml of ethanol to decompose and the volume is reduced to 100 ml. The solid was separated from the warm solution and washed with ethanol, then ether and dried at 80 ° C. in vacuo to give 435 mg of 6,7-diethoxy-4- (indan-5-ylamino) -quinoline-3-carbonitrile brown Obtained as a solid: mass spectrum (electrospray, m / e): M + H 374.0, mp = 85-88 ° C.

Example 109

4- (2,4-dioxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 274 mg of 5-aminoisotoic anhydride (1.54 mM) and 161 mg of pyridine hydrochloride in 15 ml of 2-methoxyethanol (1.44 mM) is refluxed for 3 hours. The hot solution was filtered and the solid was washed with ethanol and dried at 60 ° C. under vacuum to afford 4- (2,4-dioxo-1,4-dihydro-2H-benzo [d] [1,3] oxazine- 482 mg of HCl salt of 6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile are obtained as a gray solid: mass spectrum (electrospray, m / e): M + H 418.9, mp => 270 ° C.

Example 110

6,7-diethoxy-4- (1-oxo-indan-5-ylamino) -quinoline-3-carbonitrile

400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 227 mg (1.54 mM) of 6-amino-1-indanone and pyridine hydrochloride in 161 ml of 2-methoxyethanol 161 The mg (1.44 mM) solution is refluxed for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solids were collected, washed with water, then ether and dried at 80 ° C. under vacuum to yield 6,7-diethoxy-4- (1-oxo-indan-5-ylamino) -quinoline-3-carbo as a white solid. 483 mg of nitrile are obtained: Mass spectrum (electrospray, m / e): M + H 388.0, mp = 263 ° C. decomposition.

Example 111

6,7-diethoxy-4- (3-oxo-1,3-dihydro-isobenzofuran-5-ylamino) -quinoline-3-carbonitrile

400 mg (1.44 mM) of 6-aminophthalide, 230 mg (1.54 mM) of pyrodine hydrochloride and 161 mg of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile in 12 ml of 2-methoxyethanol The solution of was refluxed for 3 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solids were collected, washed with water, then ether and dried at 80 ° C. in vacuo to give 6,7-diethoxy-4- (3-oxo-1,3-dihydro-isobenzofuran-5-ylamino) -535 mg of quinoline-3-carbonitrile are obtained as a white solid: mass spectrum (electrospray, m / e): M + H 390.1, mp = 280-284 ° C.

Example 112

4- (1,1-dioxo-1H-benzo [b] thiophen-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile

400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 12 mg of 6-amino-1,1-dioxobenzo [b] thiophene in 12 ml of 2-methoxyethanol (1.54 mM) and 161 mg of pyridine hydrochloride are refluxed for 6 hours. 1 ml of 1 M sodium carbonate is added to the warm solution and the sample is heated at 100 ° C. for 5 minutes and then poured into 300 ml of ice water. The solids are collected, washed with water, then ether and dried at 80 ° C. under vacuum. The solid is dissolved in acetone and dried on high vacuum silica gel. Purification of the compound is accomplished by chromatography using a gradient of 30% to 50% acetone in hexanes. The first of the three components of the mixture separated from the column is the desired product. Removal of solvent by evaporation was carried out as a yellow solid, 69 mg of 4- (1,1-dioxo-1H-benzo [b] thiophen-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile. Produces: mass spectrum (electrospray, m / e): M + H 421.9, mp = 155-160 ° C.

Example 113

4- (2,3-Dihydro-1H-indol-6-ylamino) -6,7-methoxy-quinoline-3-carbonitrile

A solution of 400 mg (1.61 mM) of 6-aminoindolin dihydrochloride and 366 mg (1.77 mM) of 6-aminoindoline dihydrochloride in 12 ml of 2-methoxyethanol was added. Reflux for time. The warm solution is filtered to separate the resulting solids, which are then washed with water, then ether and dried at 80 ° C. under vacuum. The solid is dissolved in 1 to 1 methanol and chloroform and dried over high vacuum silica gel. Purification of the compound is accomplished by chromatography using a gradient of 30% to 60% acetone in hexanes. The first of the components of the mixture separated from the column is the desired product. The column fraction is reduced to 10 ml volume and then diluted with 250 ml of hexane. The resulting solid was separated, washed with hexane and dried under vacuum at 80 ° C. to 4- (2,3-dihydro-1H-indol-6-ylamino) -6,7-methoxy-quinoline as a tan solid. 16 mg of 3-carbonitrile are obtained: Mass spectrum (electrospray, m / e): M + H 347.0, mp = 175 ° C. Decomposition.

Example 114

4- (1H-Indol-5-ylamino) -6-nitro-quinoline-3-carbonitrile

A mixture of 5.00 g (21.5 mmol) of 4-chloro-6-nitro-quinolinecarbonitrile, 200 mL of ethanol and 3.40 g (25.8 mmol) of 5-aminoindole is heated under reflux for 3.5 h under N ₂ . Remove heat, basify with saturated sodium bicarbonate, strip the solvent and boil with ethanol. The solids are collected and washed with hexanes then water. The solid is dissolved in 200 ml of ethyl acetate, Darco is added and then filtered. Strip the solvent and dry in vacuo overnight (50 ° C.). Wash twice more with ether to remove starting material aminoindole. Red-brown solid 4.372 g: Mass spectrum (m / e electrospray): M + H = 330.2.

Example 115

7-ethoxy-4- (indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile

A mixture of 500 mg (1.90 mmol) of 4-chloro-7-ethoxy-6-methoxy-quinoline-3-carbonitrile, 30 ml of ethanol and 304 mg (2.28 mmol) of 6-aminoindazole was refluxed under N _{2 to} reflux. Heat. The heat is removed in 4 hours and made basic with saturated sodium bicarbonate. The solvent is stripped off, the residue slurried with hexanes, the solids are collected and then dried. Washing with water and drying in vacuo gave 546 mg of a tan solid: mass spectrum (electrospray m / e): M + H = 359.9.

Example 116

7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile

A total of 500 mg (1.63 mM) of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile was taken in 3 ml of oxalyl chloride (2M in CHCl ₃ ) and allowed to stand for 15 minutes and then 1 Reflux for time. The solution is cooled and then diluted with 300 mg of hexane to give a green solid. The solid is separated, washed with excess hexane and dried at 40 ° C. in vacuo to give 586 mg of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as the hydrogen chloride salt. This compound is taken immediately for the next step.

Example 117

7-benzyloxy-4- (2,3-dihydro-1H-indol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile

586 mg (1.60 mM) of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile in 13 ml of 2-methoxyethanol, 560 mg (1.70 mM) of 6-aminoindolin dihydrochloride salt And a solution of 208 mg (1.80 mM) of pyridine hydrochloride is refluxed for 3 hours. The reaction mixture is cooled to room temperature and the resulting solid is separated, washed with excess ethanol and dried at 80 ° C. under vacuum. The resulting solid is decomposed in 300 ml of ethanol and the volume is reduced to 100 ml. The solids are separated from the hot solution and the decomposition process is repeated a second time. The solid was once again separated from the hot solution to give 206 mg of 7-benzyloxy-4- (2,3-dihydro-1H-indol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile as a tan solid Obtained as

Example 118

4- (2,3-Dihydro-1H-indol-6-ylamino) -7-hydroxy-6-methoxy-quinoline-3-carbonitrile

To 5 ml of trifluoroacetic acid, 206 mg of 7-benzyloxy-4- (2,3-dihydro-1H-indol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile was added and the reaction mixture Reflux for 1.5 h. The TFA is removed under vacuum and the resulting film is dissolved in 7 ml of methanol and then 50 ml of ice cold saturated sodium bicarbonate is added. The solution is allowed to stand at 10 ° C. for 1 hour. The resulting solid was separated, washed with excess water and dried at 80 ° C. under vacuum to afford 4- (2,3-dihydro-1H-indol-6-ylamino) -7-hydroxy-6-methoxy- 107 mg of quinoline-3-carbonitrile are obtained. This compound is taken directly to the next step without purification.

Example 119

4- (2,3-Dihydro-1H-indol-6-ylamino) -6-methoxy-7- (3-pyridin-4-yl-propoxy) -quinoline-3-carbonitrile

2 ml of chloroform, 1 ml of tetrahydrofuran, 167 mg (0.64 mM) of triphenyl phosphine, 52 µl (0.40 mM) of 4-hydroxypropylpyridine and 4- (2,3-dihydro-1H-indole-6- To a solution consisting of 107 mg (0.32 mM) of monoamino) -7-hydroxy-6-methoxy-quinoline-3-carbonitrile is added slowly 101 μL (0.64 mM) of DEAD at 0 ° C. The reaction is conducted at 0 ° C. for 15 minutes and then warmed to room temperature. The heterogeneous solution is stirred at room temperature for 7 hours. TCL and ES MS show no signs of product formation. Additional 1 ml of chloroform and 500 ml of tetrahydrofuran are added and the reaction mixture is refluxed for 14 h. Once again there are no signs of product formation. The volume of the reaction mixture is reduced to 1 ml by heating and then to 4 ml by addition of tetrahydrofuran. When the reaction mixture is cooled to room temperature, add 80 mg (0.32 mM) of additional triphenyl phosphine, 25 μl (0.20 mM) of 4-hydroxypropylpyridine and then slowly add 50 μl (0.32 mM) of DEAD. The reaction mixture quickly turns into a clear brown solution. After 6 hours at room temperature, TLC and mass spectra indicate that the reaction is complete. To the reaction mixture is added 10 ml of 1N HCl followed by 20 ml of water. The solution is extracted five times with 25 ml fractions of chloroform. The aqueous layer is left at room temperature for 3 hours and the resulting brown solid is separated by filtration. The filtrate is treated with solid sodium bicarbonate until it is separated from the yellow solid solution. The precipitate was separated and washed with excess water, then 1 ml of diethyl ether and dried at 80 ° C. under vacuum to afford 4- (2,3-dihydro-1H-indol-6-ylamino) -6-methoxy- 57 mg of 7- (3-pyridin-4-yl-propoxy) -quinoline-3-carbonitrile are obtained as a yellow solid: mass spectrum (electrospray, m / e): 452.3 M + H, 226.7 M + 2H / 2, mp = 100-105 ° C.

Example 120

2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid methyl ester

19.6 g (109 mmol) of 2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid (J. Chem. Soc., 3445, 1957) in 400 ml of MeOH containing 4 ml of H ₂ SO ₄ The solution of is refluxed overnight. Sodium bicarbonate (18 g) is added, the solvent is removed and the residue is triturated several times with Et ₂ O. The washes were combined, filtered through anhydrous MgS0 ₄ and evaporated to afford 20.7 g of the title compound as a pale yellow oil: mass spectrum (electron impact, m / e): 194.

Example 121

7-nitro-2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid methyl ester

Nitric acid (18 mL) is added dropwise to a solution of 15.0 g (77.3 mmol) of 2,3-dihydro-benzo [1,4] dioxine-6-carboxylic acid methyl ester in 45 mL of HOAc. The solution is heated at 60 ° C. for 1.5 h. Then 9 ml of additional HNO ₃ are added and heating is continued at 70 ° C. for 1.5 h. The reaction mixture is poured into ice-H ₂ O and the solid product collected, washed well with H ₂ O and dried. Recrystallization from heptane-toluene yields 16.8 g of the title compound as yellow crystals: mass spectrum (electron impact, m / e): 239.

Example 122

7-amino-2,3-dihydro-benzo [1,4] dioxin-6-carboxylic acid methyl ester

12.0 g (50.2 mmol) of 7-nitro-2,3-dihydro-benzo [1,4] dioxine-6-carboxylic acid methyl ester in 175 mL of MeOH and 70 mL of H ₂ O, 11.2 g (201 mmol) of powdered Fe And 13.3 g (257 mmol) of NH ₄ Cl are refluxed for 5.5 h. An additional 11.2 g of Fe and 13.3 g of NH ₄ Cl are added and the mixture is further heated for 5.5 h. Finally, 5.5 g of Fe and 6.5 g of NH ₄ Cl are added and the mixture is heated for 4 hours. The cooled reaction mixture is filtered through celite, the pad is washed well with MeOH and the filtrate and wash are combined. The solvent is removed and the residue is slurried in H ₂ O and collected. The crude product was filtered through silica (CHCl ₃ ) to give 9.5 g of the title compound as tan crystals: mass spectrum (electrospray, m / e): M + H 209.9.

Example 123

9-oxo-2,3,6,9-tetrahydro- [1,4] dioxino [2,3-g] quinoline-8-carbonitrile

A solution of 9.71 g (46.5 mmol) and 11.1 g (92.9 mmol) of dimethylformamide dimethyl acetal in 7-amino-2,3-dihydro-benzo [1,4] dioxine-6-carboxylic acid methyl ester in 45 ml of DMF was added. Reflux under N _{2 for} 6 hours. The volatiles are removed and the residue is boiled with toluene and dried in vacuo to give formamidine as a purple syrup.

N-butyllithium (102 mmol) in hexane is diluted with 70 mL THF at -78 ° C under N ₂ . A solution of 4.31 g (105 mmol) of acetonitrile in 85 mL of THF is added over 15 minutes and the solution is stirred for 25 minutes. Crude formamidine is dissolved in 90 ml of THF and added dropwise to the cold solution over 0.5 hour. After stirring for 1.25 h, the reaction mixture is cooled to 13.4 mL of acetic acid at -78 ° C. It is warmed to room temperature and the volatiles are removed in vacuo. The residue is slurried with H ₂ O and the crude product is collected by filtration, washed with H ₂ O and dried. The solid material is boiled with MeOH, collected and dried in vacuo (50 ° C.) to give 7.62 g of the title compound as a tan powder: mass spectrum (electrospray, m / e): M + H 228.8.

Example 124

9-chloro-2,3-dihydro [1,4] dioxino [2,3-g] quinoline-8-carbonitrile

A mixture of 7.06 g (31.0 mmol) of WAY 170839 and 35 mL of POCl ₃ was refluxed for 3.5 h. POCl ₃ is removed, ice-H ₂ O is added and solid NaHCO ₃ is added to pH 8. The product was collected, washed well with H ₂ O and dried in vacuo to give 7.42 g of 9-chloro-2,3-dihydro [1,4] dioxino [2,3-g] quinoline-8-carbonitrile. Is obtained as a tan solid: mass spectrum (electrospray, m / e): M + H 246.8.

Example 125

9- (1H-indazol-6-ylamino) -2,3-dihydro [1,4] dioxino [2,3-g] quinoline-8-carbonitrile

1.00 g (4.07 mmol) of 9-chloro-2,3-dihydro [1,4] dioxino [2,3-g] quinoline-8-carbonitrile and 0.649 g of 6-aminoindazole in 25 ml of EtOH ( 4.88 mmol) is refluxed under N _{2 for} 5.7 h. Saturated NaHCO ₃ is added and the solvent is removed. The residue is slurried with H ₂ O, filtered and washed with H ₂ O and cold EtOH and dried. The crude product was boiled with EtOH, filtered and dried in vacuo (50 ° C.) to give 9- (1H-indazol-6-ylamino) -2,3-dihydro [1,4] dioxino- [ 1.06 g of 2,3-g] quinoline-8-carbonitrile are obtained as tan crystals: mass spectrum (electrospray, m / e): M + H 344.3.

Example 126

6-ethoxy-4- (1H-indazol-6-ylamino) -7-methoxyquinoline-3-carbonitrile

A mixture of 1.00 g (3.82 mmol) of 4-chloro-6-ethoxy-7-methoxyquinoline-3-carbonitrile and 0.609 g (4.58 mmol) of 6-aminoindazole in 20 ml of EtOH was added under N _{2 for} 8 hours. Reflux. Saturated NaHCO ₃ is added, the solvent is removed and the residue is boiled twice with EtOH. The solid is slurried with cold EtOH, collected, washed twice with H ₂ O and dried. Recrystallization from EtOH yields 0.646 g of 6-ethoxy-4- (1H-indazol-6-ylamino) -7-methoxyquinoline-3-carbonitrile as tan crystals: mass spectrum (electrospray, m / e): M + H 359.9.

Example 127

6,7-diethoxy-4- (1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [e] [1,4] diazepin-7-ylamino ) -Quinoline-3-carbonitrile

0.5 g (1.8 mmol) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 7-amino-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro- A mixture of 0.35 g (1.8 mmol) of 1H-benzo [e] [1,4] diazepine and 0.21 g of pyridine hydrochloride is refluxed in ethoxyethanol for 5 hours. The solvent is removed at reduced pressure. The residue was stirred with ammonium hydroxide and the insoluble material was collected to give 0.8 g of the title compound as a tan solid: Crystals: mass spectrum (electrospray, m / e): M + H 446.0.

Example 128

4- (1H-indazol-6-ylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile

A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.147 g of 6-aminoindazole, 0.020 g of pyridine hydrochloride and 15 mL of ethoxyethanol was added at reflux under nitrogen Stir for 1 hour. Cool the mixture and add 100 ml of water. To this mixture is added sodium carbonate to pH 9. The product was collected, washed with water and dried to give 0.332 g of 4- (1H-indazol-6-ylamino) -6,7,8-trimethoxy-quinolin-3-carbonitrile as a solid, mp 243-245 ° C .; Mass spectrum (EI, m / e): M 375.1331.

Example 129

6,7-Dimethoxy-4- (4-methyl-2-oxo-1,2-dihydro-quinolin-7-ylamino) -quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, carbostyryl 124, 0.174 g, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was stirred at reflux under nitrogen for 30 minutes. Stir. The mixture is cooled and added to 40 ml of water. To this mixture is added sodium carbonate to pH 9. The product was collected, washed with water and dried to give 6,7-dimethoxy-4- (4-methyl-2-oxo-1,2-dihydro-quinolin-7-ylamino) -quinoline-3-carbo 0.356 g of nitrile is obtained as a solid, mp> 300 ° C .; Mass spectrum (electrospray, m / e): M + H 387.1446.

Example 130

6,7-dimethoxy-4- (2-methyl-benzothiazol-5-ylamino) -quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.237 g of 5-amino-2-methylbenzothiazole dihydrochloride, 0.158 g of pyridine and 10 ml of ethoxyethanol was added under nitrogen. Stir at reflux for 20 minutes. The mixture is cooled and added to 40 ml of water. To this mixture is added sodium carbonate to pH 9. The product was collected, washed with water and dried to give 0.356 g of 6,7-dimethoxy-4- (2-methyl-benzothiazol-5-ylamino) -quinoline-3-carbonitrile as a solid, mp 118-120 ° C .; Mass spectrum (EI, m / e): M 376.0973.

Example 131

6,7-Dimethoxy-4- (2-oxo-2,3-dihydro-benzothiazol-6-ylamino) -quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.166 g of 6-amino-2-benzothiazolinone, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was refluxed under nitrogen. Stir at temperature for 20 minutes. The mixture is cooled and added to 40 ml of water. The mixture is adjusted to pH 7 by addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and dried to give 0.326 g of 6,7-dimethoxy-4- (2-oxo-2,3-dihydro-benzothiazol-6-ylamino) -quinoline-3-carbonitrile To a solid, mp 285-287 ° C .; Mass spectrum (electrospray, m / E): M + H 379.0858.

Example 132

6,7-dimethoxy-4- (quinolin-5-ylamino) -quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.288 g of 5-aminoquinoline, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was added at 200 ° C. under nitrogen in a closed tube. Heat for hours. The mixture is cooled and added to 100 ml of water. To this mixture is added sodium carbonate to pH 9. The product was collected, washed with water and dried to give 0.132 g of 6,7-dimethoxy-4- (quinolin-5-ylamino) -quinoline-3-carbonitrile as a solid, mp 115 ° C. (decomposition) ; Mass spectrum (EI, m / e): M 356.1276.

Example 133

4- (isoquinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.288 g of 5-aminoisoquinoline, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was added to a sealed tube at 200 ° C. under nitrogen. Heat for 2 hours. The mixture is cooled and added to 100 ml of water. To this mixture is added sodium carbonate to pH 9. The product was collected, washed with water and dried to yield 0.100 g of 4- (isoquinolin-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile as a solid, mp 140 ° C. (decomposition) ; Mass spectrum (EI, m / e): M 356.1279.

Example 134

6,7-dimethoxy-4- (quinolin-8-ylamino) -quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.288 g of 8-aminoquinoline, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was added at 200 ° C. under nitrogen in a closed tube. Heat for hours. The mixture is cooled and added to 100 ml of water. To this mixture is added sodium carbonate to pH 9. The product was collected, washed with water and dried to give 0.167 g of 6,7-dimethoxy-4- (quinolin-8-ylamino) -quinoline-3-carbonitrile as a solid, mp 150 ° C. (decomposition) ; Mass spectrum (EI, m / e): M 356.1271.

Example 135

4- (8-hydroxy-quinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.233 g of 5-amino-8-hydroxyquinoline dihydrochloride, 0.158 g of pyridine and 10 ml of ethoxyethanol was refluxed under nitrogen. Stir at temperature for 2 hours. The mixture is cooled and added to 40 ml of water. The mixture is adjusted to pH 7 by addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and dried to give 0.210 g of 4- (8-hydroxy-quinolin-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 150 ° C. (decomposition); Mass spectrum (EI, m / e); M 372.1228.

Example 136

4- (1H-Indol-4-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.132 g of 4-aminoindole, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was stirred at reflux temperature under nitrogen for 2 hours. do. The mixture is cooled and added to 40 ml of water. The mixture is adjusted to pH 7 by addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and dried to yield 0.249 g of 4- (1H-indol-4-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 260 ° C. ( decomposition); Mass spectrum (EI, m / e): M 344.1282.

Example 137

4- (1H-indazol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile

A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.132 g of 5-aminoindazole, 0.020 g of pyridine hydrochloride and 10 ml of ethoxyethanol was added at reflux under nitrogen for 2 hours. Stir. The mixture is cooled and added to 40 ml of water. The mixture is adjusted to pH 7 by addition of sodium carbonate and concentrated hydrochloric acid. The product was collected, washed with water and dried to afford 0.252 g of 4- (1H-indazol-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile as a solid, mp 290- 295 ° C .; Mass spectrum (EI, m / e): M 345.1217.

Example 138

4- (1H-indazol-6-ylamino) -5,8-dimethoxy-quinoline-3-carbonitrile

A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-quinoline-3-carbonitrile, 0.093 g of 6-aminoindazole and 5 ml of ethoxyethanol is stirred at reflux under nitrogen for 30 minutes. The mixture is cooled and added to 50 ml of water. To this mixture is added pH 9 sodium carbonate. The product was collected, washed with water, dried and washed with 10 ml of hexane-ethyl acetate (4: 1) to give 4- (1H-indazol-6-ylamino) -5,8-dimethoxy-quinoline-3 0.189 g of carbonitrile are obtained as a solid, mp 302-305 ° C .; Mass spectrum (EI, m / e): M 345.1223.

Example 139

4- (1H-indazol-6-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile hydrochloride

A mixture of 0.362 g of 4-chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile, 0.267 g of 6-aminoindazole and 10 ml of ethoxyethanol Stir for 30 minutes at reflux under nitrogen. The mixture is cooled and added to 50 ml of a mixture of ethyl acetate / acetone / methyl alcohol (5: 5: 2). The product was collected, washed with water, dried and washed with 10 ml of hexane-ethyl acetate (4: 1) 4- (1H-indazol-6-ylamino) -7-methoxy-6- (3- 0.189 g of morpholin-4-yl-propoxy) -quinoline-3-carbonitrile hydrochloride is obtained as a solid, mp 100 ° C. (decomposition); Mass spectrum (electrospray, m / e): M + H 459.2146.

Example 140

4- (3H-Benzotriazol-5-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile hydrochloride

A mixture of 0.362 g of 4-chloro-7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile, 0.268 g of 5-aminobenzotriazole and 10 ml of ethoxyethanol Is stirred at reflux under nitrogen for 30 minutes. The mixture is cooled and added to 50 ml of a mixture of ethyl acetate / acetone / methyl alcohol (5: 5: 2). The product was collected, washed with water, dried and washed with 10 mL of hexane-ethyl acetate (4: 1) to give 4- (3H-benzotriazol-6-ylamino) -7-methoxy-6- (3 0.142 g of morpholin-4-yl-propoxy) -quinoline-3-carbonitrile hydrochloride is obtained as a solid, mp 260 ° C. (decomposition); Mass spectrum (electrospray, m / e): M + H 460.2096.

Example 141

4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile

115.6 mg (1.0 mmol) of pyridine hydrochloride in a suspension of 218.6 mg (1.0 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile and 159.8 mg (1.2 mmol) of 6-aminoindazole in 10 mL of 2-ethoxyethanol. mmol) is added. The resulting reaction mixture is refluxed for 1 hour. After cooling, most of the solvent is evaporated and the residue is diluted with ether. The precipitate is collected by filtration and taken up in water. The aqueous suspension is neutralized to pH 7-8 by addition of saturated aqueous sodium carbonate solution and stirred for 15 minutes. The separated solid is filtered off and washed with water and ether. After drying in vacuo, 297.5 mg (94.3%) of product are obtained as a deep yellow solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 315.8. HRCIMS m / z: Calcd for C ₁₈ H ₁₃ N ₅ 0 (M ⁺ ) 315.112, found 315.1124.

Example 142

4- (3H-Benzotriazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol was added to 161.0 mg of 5-aminobenzotriazole. (1.2 mmol) in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride to give 302.9 mg (95.8%) of the product as a yellow solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 316.9. HRCIMS calcd: Calcd for C ₁₇ H ₁₂ N ₆ O (M ⁺ ) 316.107, found 316.1081.

Example 143

4- (1H-indazol-6-ylamino) -7-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 141, 200.0 mg (0.914 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol was added to 105.6 mg (0.914 mmol) of pyridine hydrochloride. Reaction with 147.8 mg (1.1 mmol) of 6-aminoindazole in the presence of c) yields 280.0 mg (97.3%) of the product as a deep yellow solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 315.9 HRCIMS: Calcd for C ₁₈ H ₁₃ N ₅ 0 (M ⁺ ) 315.112, found 315.1124.

Example 144

4- (3H-Benzotriazol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 141, 218.6 mg (1.0 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol was added to 115.6 mg (1.0 mmol) of pyridine hydrochloride. Reaction with 161.0 mg (1.2 mmol) of 5-aminobenzotriazole in the presence of) yields 231.0 mg (73.1%) of the product as a pale brown solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 316.9 HRCIMS: Calcd for C ₁₇ H ₁₂ N ₆ O (M ⁺ ) 316.107, found 316.1063.

Example 145

7-hydroxy-4- (1H-indazol-6-ylamino) -quinoline-3-carbonitrile

A reaction mixture of 1.74 g (5.52 mmol) of 4- (1H-indazol-6-ylamino) -7-methoxy-quinoline-3-carbonitrile and 15.3 g of pyridine hydrochloride was heated at 200-210 ° C. for 1.5 hours. do. After cooling, the mixture is taken up in an aqueous 3% NH ₄ OH solution. The precipitate is collected by filtration and washed with water. 1.66 g (63.8%) of product is obtained after drying in vacuo as a deep brown solid, mp> 250 ° C .; Mass spectrum (electrospray, m / e): M + H 301.9 HRCIMS: Calcd for C ₁₇ H ₁₁ N ₅ O (M ⁺ ) 302.1042, found 302.1079.

Example 146

4- (1H-Indol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 141, 1.0 g (4.57 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile, 724.8 mg (5.48) of 5-aminoindole in 35 ml of 2-ethoxyethanol mmol) and 528.3 mg (4.57 mmol) of 5-aminoindole are heated at 120 ° C. for 2 hours. This operation yields 1.38 g of product as a green-grey solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 314.9 HRCIMS: calculation for C ₁₉ H ₁₄ N ₄ O (M ⁺ ) Found 314.117, found 314.1135.

Example 147

7-hydroxy-4- (3H-benzotrizol-5-ylamino) -quinoline-3-carbonitrile

Using a procedure similar to that described in Example 145, 1.45 g (4.58 mmol) of 4- (3H-benzotrizol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile and pyridine hydrochloride 10 Heat g for 1 hour. This operation produces 1.04 g (75.4%) of the product as a dark brown solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 303.3 HRCIMS: C ₁₆ H ₁₀ N ₆ O (M ⁺ Calculated for 301.0838, found 301.0833.

Example 148

4- (1H-indazol-6-ylamino) -8-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 141, 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile in 15 ml of 2-ethoxyethanol, 219.7 mg of 6-aminoindazole ( 1.65 mmol) and 105.6 mg (173.3 mmol) of pyridine hydrochloride are heated at 100 ° C. for 2 hours. This operation produces 373.8 mg (79%) of the product as a yellow solid, mp> 250 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 315.9 HRCIMS: C ₁₈ H ₁₃ N ₅ O ( Calculated for M ⁺ ) 315.112, found 315.1126.

Example 149

4- (3H-Benzotriazol-5-ylamino) -8-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol, 161.0 mg of 5-aminobenzotriazole (1.2 mmol) and 115.6 mg (1 mmol) of pyridine hydrochloride are heated at 100 ° C. for 1 hour. This operation produces 213.5 mg (67.6%) of the product as a yellow solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 316.9 HRCIMS: C ₁₇ H ₁₂ N ₆ O (M ⁺ ) Calculated for 316.107, found 316.1079.

Example 150

4- (1H-Indol-5-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 141, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 ml of 2-ethoxyethanol, 158.6 mg of 5-aminoindole (1.2 mmol) and 115.6 mg (1 mmol) of pyridine hydrochloride are refluxed for 0.5 h. This operation produces the product 338.7 mg (98.5%) as a yellow solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 344.9 HRCIMS: C ₂₀ H ₁₆ N ₄ O ₂ (M ⁺ Calculated for 344.127, measured 344.1277.

Example 151

4- (1H-Benzoimidazol-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile

Using a procedure similar to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 ml 2-ethoxyethanol, 5-aminobenzoimidazole 159.8 mg (1.2 mmol) and 115.6 mg (1 mmol) of pyridine hydrochloride are refluxed for 1 hour. This operation produces the product 233.6 mg (67.7%) as a brown solid, mp 230 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 345.9 HRCIMS: C ₁₉ H ₁₅ N ₅ O ₂ ( M ⁺ ) calculated 346.1304, measured 346.1325.

Example 152

6,7-dimethoxy-4- (2-methyl-1H-benzoimidazol-5-ylamino) -quinoline-3-carbonitrile

Using a procedure similar to that described in Example 150, 248.7 mg (1 mmol) 4-methyl-6,7-dimethoxy-3-quinolinecarbonitrile in 10 ml 2-ethoxyethanol, 2-methyl-5- 294.4 mg (2.0 mmol) of aminobenzimidazole and 115.6 mg (1 mmol) of pyridine hydrochloride are refluxed for 4 hours. This operation produces 220.2 mg (61.3%) of the product as a sandy solid, mp 207 ° C (decomposition), mass spectrum (electrospray, m / e): M + H 359.9 HRCIMS: C ₂₀ H ₁₇ N ₅ O ₂ ( M ⁺ ) calculated 359.138, found 359.1403.

Example 153

6,7-dimethoxy-4- (quinolin-6-ylamino) -quinoline-3-carbonitrile

Using a procedure similar to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 ml of 2-ethoxyethanol, 173.8 mg of 6-aminoquinoline (1.2 mmol) and 115.6 mg (1 mmol) of pyridine hydrochloride are refluxed for 6 hours. This operation produces 212.5 mg (59.5%) of the product as an orange solid, mp 241-243 ° C., mass spectrum (electrospray, m / e): M + H 356.8 HRCIMS: C ₂₀ H ₁₇ N ₅ O ₂ (M Calculated for ⁺ ) 356.127, measured 356.1275.

Example 154

4- (4-Chloro-naphthalen-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 150, 248.7 mg (1 mmol), 1-amino-4- 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 ml 2-ethoxyethanol 213.2 mg (1.2 mmol) of chloronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride are refluxed overnight. This operation produces the product 290.1 mg (74.4%) as a greenish yellow solid, mp> 250 ° C., mass spectrum (electrospray, m / e): M + H 390.2 HRCIMS: C ₂₂ H ₁₆ N ₃ O ₂ Cl (M calculated values for ⁺⁾ 389.093, measured value 389.0938.

Example 155

6,7-dimethoxy-4- (5,6,7,8-tetrahydro-naphthalen-1-ylamino) -quinoline-3-carbonitrile

Using a procedure similar to that described in Example 150, 248.7 mg (1 mmol), 1-amino-5, 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 ml 2-ethoxyethanol, 176.7 mg (1.2 mmol) of 6,7,8-tetrahydronaphthalene and 115.6 mg (1 mmol) of pyridine hydrochloride are refluxed for 2 hours. This operation produces the product 195.1 mg (54.3%) as a yellow solid, mp 248 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 360.1 HRCIMS: C ₂₂ H ₁₆ N ₃ O ₂ Cl Calculated value for (M ⁺ ) 359.163, found 359.1632.

Example 156

4- (3H-Benzotriazol-5-ylamino0-6,7,8-trimethoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 150, 278.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 ml 2-ethoxyethanol, 5-aminobenzotriazole 161.3 mg (1.2 mmol) and 115.6 mg (1 mmol) of pyridine hydrochloride are refluxed for 10 minutes. This operation produces 246.3 mg (65.4%) of the product as a yellow solid, mp 205 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 376.9 HRCIMS: C ₁₉ H ₁₆ N ₆ O ₃ ( M ⁺ ) calculated 376.128, found 376.1264.

Example 157

4- (1H-indazol-6-ylamino) -6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy] -quinoline-3-carbonitrile

196.5 mg (0.5 mmol), 1-methyl 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile in 10 ml DME 500.9 mg (5 mmol) of piperazine and 74.5 mg (0.5 mmol) of sodium iodine are heated in a closed tube at 135 ° C. under N ₂ for 15 hours. After cooling, the solvent is removed and the residue is taken up in 15 ml brine. The aqueous solution is extracted with 15% methanol / methylene chloride. The organic solvent is dried over Na ₂ SO ₄ and filtered. Removal of the solvent produces a crude solid. Purification of the crude product on preparative TLC (development solvent: 15% methanol / methylene chloride) yields a yellow foam solid. Polishing of the foam solids with ether gave 117.9 mg (51.6%) of the product as a yellow solid, mp 179 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 458.0.

Example 158

7- {2-[(2-hydroxy-ethyl) -amino] -ethoxy} -4 (1H-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 5 ml of DME. 196.5 mg (0.5 mmol) of carbonitrile, 375.6 mg (5.0 mmol) of 2- (methylamino) -ethanol and 75.0 mg (0.5 mmol) of sodium iodine are heated at 135 ° C. for 15 hours. This operation produces 116.4 mg (54.0%) of the product as a yellow solid, m.p. 179 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 433.0.

Example 159

7- {2- [bis- (2-hydroxy-ethyl) -amino] -ethoxy} -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 6 ml DME 196.5 mg (0.5 mmol) of carbonitrile, 525.7 mg (5.0 mmol) of diethanolamine and 75.0 mg (0.5 mmol) of sodium iodine are heated at 135 ° C. for 15 hours. This operation produces 109.1 mg (47.2%) of the product as a yellow solid, m.p. 150 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 463.0.

Example 160

7- [2- (4-hydroxy-piperidin-1-yl) -ethoxy] -4- (indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 5 ml of DME. 196.5 mg (0.5 mmol) of carbonitrile, 505.8 mg (5.0 mmol) of 4-hydroxypiperidine and 75.0 mg (0.5 mmol) of sodium iodine are heated at 135 ° C. for 16 h. This operation produces 97.9 mg (42.8%) of the product as an off-white solid, m.p. 174 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 459.0.

Example 161

7- {2-[(4-hydroxy-ethyl) -piperazin-1-yl) -ethoxy] -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3- Carbonitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 5 ml of DME. 196.5 mg (0.5 mmol) of carbonitrile, 651.0 mg (5.0 mmol) of 1- (2-hydroxyethyl) piperazine and 75.0 mg (0.5 mmol) of sodium iodine are heated at 135 ° C. for 16 hours. This operation produces 90.5 mg (37.1%) of the product as a yellow solid, m.p. 174 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 488.0.

Example 162

7- [2- (1,4-Dioxa-8-aza-spiro [4,5] dec-8-yl) -ethoxy] -4- (1H-indazol-6-ylamino) -6- Methoxy-quinoline-3-carbonitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 5 ml of DME. 196.5 mg (0.5 mmol) of carbonitrile, 716.0 mg (5.0 mmol) of 1,4-dioxa-8-azaspiro [4,5] decane and 75.0 mg (0.5 mmol) of sodium iodine were heated at 135 ° C. for 16 hours do. This operation produces 173.1 mg (69.2%) of the product as an off-white solid, m.p. 245 ° C. (decomposition), mass spectrum (electrospray, m / e): M + H 501.0.

Example 163

4- (1H-indazol-6-ylamino) -6-methoxy-7- (2-thiomorpholin-4-yl-ethoxy) -quinoline-3-carbonitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 4 ml of DME. 173.0 mg (0.44 mmol) of carbonitrile, 454.0 mg (4.4 mmol) of thiomorpholine and 66.0 mg (0.44 mmol) of sodium iodine are heated at 135 ° C. for 16 hours. This operation produces the product 108.4 mg (53.5%) as a pale yellow solid, m.p. 213-215 ° C., mass spectrum (electrospray, m / e): M + H 461.0.

Example 164

7- [2-([1,3] dioxolan-2-ylmethyl-methyl-amino) -ethoxy] -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 Carbonnitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 4 ml of DME. 173.0 mg (0.44 mmol) of carbonitrile, 515.5 mg (4.4 mmol) of 2-([1,3] -dioxolan-2-ylmethyl-methylamine and 66.0 mg (0.44 mmol) of sodium iodine at 135 ° C. for 16 hours This operation produces 136.1 mg (65.2%) of the product as a yellow solid, mp 185-187 ° C., mass spectrum (electrospray, m / e): M + H 475.1.

Example 165

7- [2- (3,4-Dihydro-1H-isoquinolin-2-yl) -ethoxy] -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3- Carbonitrile

Using a procedure similar to that described in Example 157, 7- (2-chloro-ethoxy) -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3 in 4 ml of DME. 173.0 mg (0.44 mmol) of carbonitrile, 586.0 mg (4.4 mmol) of 1,2,3,4-tetrahydroisoquinoline and 66.0 mg (0.44 mmol) of sodium iodine are heated at 135 ° C. for 16 hours. This operation produces 109.3 mg (50.6%) of the product as a yellow solid, m.p. 170-173 ° C., mass spectrum (electrospray, m / e): M + H 491.0.

Example 166

7- (2-chloroethoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile

0.50 g (1 equiv) of 7- (2-chloro-ethoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.25 g (1.1 equiv) of 6-aminoindazole, 0.22 g pyridine hydrochloride (1.1 equiv) and 15 mL of 2-methoxyethanol are heated in a 120 ° C. oil bath for 2 hours. The reaction progress is monitored by thin layer chromatography (acetone / hexane 1: 1). After 2 hours, the reaction mixture is cooled to room temperature; A total of 25 ml of 1 M sodium bicarbonate is added and the reaction mixture is stirred for 1 hour. The resulting precipitate is collected, washed with water and dried overnight at 60 ° C. in vacuo to yield 0.645 g (97%) of the desired product: mass spectrum (electrospray m / e): M + H = 393.9 (M + H ) ⁺ ; Anal calculated for C ₂₀ H ₁₆ ClN ₅ O ₂ : 2 H ₂ O: calculated C: 55.88; H: 4.69; N: 16.29; Actual C: 55.63; H: 4.78; N: 15.24.

Example 167

7- (2-dimethylaminoethoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile

0.67 g (1 equiv) of 7- (2-chloroethoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile in tetrahydrofuran, 0.097 g of sodium iodine ( 0.4 equivalent) and 15 ml of 2 M dimethylamine are heated at 135 ° C. in a closed tube for 14 hours. The reaction mixture is diluted with ethyl acetate, washed with saturated sodium bicarbonate, and the organic layer is dried over magnesium sulphate and concentrated to give 0.50 g. The crude product is purified by chromatography (silica gel: ethyl acetate, ethyl acetate / methyl alcohol / triethylamine 6: 4: 0.1) to give 0.312 g (46%) of the pure product.

MP 218-219 ° C .: Mass spectrum (electrospray m / e): M + H = 402.9.

Example 168

4- (1H-indazol-6-ylamino) -6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinoline-3-carbonitrile

0.616 g of 7- (2-chloroethoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile, 0.094 g of sodium iodine and 2.03 ml of morpholine were added to the title compound. Prepared by the procedure of Example 167 to give 0.196 g (28%) of the desired product after purification by chromatography (silica gel: ethyl acetate, ethyl acetate / methyl alcohol / triethylamine 6: 4: 0.1). . MP 133-135 ° C .: Mass spectrum (electrospray m / e): M + H = 445.0.

Example 169

4- (3H-benzotriazol-5-ylamino) -7- (2-chloroethoxy) -6-methoxyquinoline-3-carbonitrile

The title compound was diluted with 0.442 g of 7- (2-chloro-ethoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.22 g of 5-aminobenzotriazole, 0.190 g of pyridine hydrochloride and 2-meth Prepared in the procedure of Example 166 using 15 ml of oxyethanol to afford 0.48 g (82%) of the desired product: Mass spectrum (electrospray m / e): M + H = 394.8.

Example 170

7- (3-chloropropoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile

The title compound was prepared with 0.311 g of 7- (3-chloro-propoxy) -4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.147 g of 6-aminoimidazole, 0.128 g of pyridine hydrochloride and ethoxyethanol 12 Prepared in the procedure of Example 166 using mL to yield 0.367 g (90%) of the desired product. MP 280-285 ° C .: Mass spectrum (electrospray m / e): M + H = 407.9.

Example 171

4- (1H-indazol-6-ylamino) -6-methoxy-7- (3-morpholin-4-ylpropoxy) quinoline-3-carbonitrile

The title compound was diluted with 0.408 g of (3-chloropropoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile, 1.4 ml of morpholine, 0.060 g of sodium iodine and ethylene glycol Prepared in the procedure of Example 167 using 12 ml of dimethyl ether to afford 0.255 g (56%) of the desired product. MP 143-145 ° C .; HRMS: C ₂₅ H ₂₆ N ₆ O ₃ : m / z 458.2084; δ (mu) -1.7.

Example 172

4- [3-chloro-4- (1-methyl-2-imidazolylthio) phenylamino] -6,7-diethoxy-3-quinolinecarbonitrile

Reaction of 4-chloro-6,7-diethoxy-3-quinoline-carbonitrile with 3-chloro-4- (1-methyl-2-imidazolylthio) aniline (WO-9615118) by the method of Example 141 Yields the title compound as a tan solid, mp 285-290 ° C.

Example 173

4- [3-chloro-4- (1-methyl-2-imidazolylthio) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile

Reaction of 4-chloro-6,7-dimethoxy-3-quinoline-carbonitrile with 3-chloro-4- (1-methyl-2-imidazolylthio) aniline (WO-9615118) by the method of Example 141 Yields the title compound as a white solid, mp 302-307 ° C.

Example 174

4- [3-Chloro-4- (1-methyl-1H-imidazol-2-ylsulfanyl) -phenylamino] -6-nitro-quinoline-3-carbonitrile

5.00 g (21.5 mmol) of 4-chloro-6-nitro-3-quinolinecarbonitrile, 250 ml of ethanol and 3-chloro-4- (1-methyl-1H-imidazol-2-ylsulfanyl) -aniline (WO -9615118) 6.18 g of the mixture is heated to reflux under N ₂ . Heat is removed in 3½ hours and made basic with saturated sodium bicarbonate solution. Strip the solvent and boil with ethanol. The residue is slurried with hexanes and the solids are collected. Wash with water and dry in vacuo. Boil the solid in hexane to remove excess aniline and air dry. Boil in 2 L ethyl acetate and, due to severe insolubility, collect the solid and dry in vacuo to give 5.90 g of a yellow solid: mass spectrum (electrospray, m / e): M + H = 437.2, 439.1.

Example 175

6-Amino-4- [3-chloro-4- (1-methyl-1 H-imidazol-2-ylsulfanyl) -phenylamino] -quinoline-3-carbonitrile

4.734 g (13.1 mmol) of 4- [3-chloro-4- (1-methyl-1H-imidazol-2-ylsulfanyl) -phenylamino] -6-nitro-quinoline-3-carbonitrile, 250 ml of ethanol And 14.83 g (65.6 mmol) of tin chloride dihydrate are heated to reflux under N ₂ . Heat is removed in 2½ hours and a large amount of ice water is added. Make basic with sodium bicarbonate and stir for 2 hours. The still basic mixture is extracted with chloroform and the organic layer is stirred with Darco, then dried over sodium sulfate and filtered. Strip the solvent and dry in vacuo to give 2.86 g of a tan solid: mass spectrum (electrospray m / e): M + H = 407.3, 409.3.

Example 176

N- {4- [3-Chloro-4- (1-methyl-1H-imidazol-2-ylsulfanyl) -phenylamino] -3-cyano-quinolin-6-yl} -acrylamide

1.00 g (2.46 mmol) of 6-amino-4- [3-chloro-4- (1-methyl-1H-imidazol-2-ylsulfanyl) -phenylamino] -quinoline-3-carbonitrile Dissolve in 3.5 ml of DMF, add 12 ml of THF and then cool to 0 ° C. 377 μl triethyl amine and 225 μl (2.70 mmol) of acryloyl chloride are added. Remove the ice bath at 15 minutes and strip the solvent at 2 hours. The residue is slurried in water, solids are collected and then air dried overnight. Boil in ethyl acetate, collect the solid and then dry in vacuo to give 670 mg of a tan solid: mass spectrum (electrospray m / e): M + H = 461.1, 462.2.

Example 177

6-amino-4- (1H-indol-5-ylamino) -quinoline-3-carbonitrile

200 mg of 10% palladium on carbon is covered with 75 ml of ethanol. 2.00 g (6.07 mmol) of 4- (1H-indol-5-ylamino) -6-nitro-quinoline-3-carbonitrile and 477 μl (15.2 mmol) of hydrazine are added. Heat to reflux under N ₂ for 2 h. The hot solution is filtered through celite and washed with hot methanol. The solvent was removed and dried in vacuo (50 ° C.) to give 1.89 g of a brown solid: mass spectrum (m / e electrospray): M + H = 300.2.

Example 178

3-chloro-4- (1,3-thiazol-2-ylsulfanyl) aniline

To a suspension of 3.8 g of sodium hydride (60% in mineral oil) in 100 ml of dimethylformamide, a solution of 10.0 g of 2-mercaptothiazole in 100 ml of dimethylformamide is slowly added. After 15 minutes a solution of 15.0 g of 3-chloro-4-fluoronitrobenzene in 50 ml of dimethylformamide is added. After 4 hours, the mixture is poured into water. The resulting solids are collected, washed with water and dried in vacuo. This material is mechanically stirred at reflux for 4 hours in a mixture of 830 ml of methanol, 230 ml of water, 37.0 g of ammonium chloride and 30.1 g of iron powder. The boiling mixture is filtered. The solvent is removed from the filtrate and the residue is extracted with hot ethyl acetate. The ethyl acetate solution is filtered through a silica gel short column. The solvent was removed and the residue was recrystallized from ether hexane to give 17.7 g of an off-white solid: mass spectrum (electrospray, m / e): M + H 243.1.

By using a procedure similar to that described above, the following intermediates necessary to prepare some of the compounds of the present invention can be prepared.

3-chloro-4- (1H-imidazol-1-yl) aniline

2-[(4-amino-2-chlorophenyl) sulfanyl] -4 (3H) -quinazolinone

N- (4-amino-2-chlorolphenyl) -N- (3-pyridinylmethyl) acetamide

2-chloroN-1- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] -1,4-benzenediamine

3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] aniline

3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] aniline

4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) aniline

4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (chloro) aniline

Example 179

1- (2-chloro-4-aminobenzyl) -1H-imidazole

A solution of 10 g of 4-bromomethyl-3-chloro nitrobenzene and 5.44 g of imidazole in 125 ml of tetrahydrofuran is refluxed for 4 hours. The solvent is removed and the residue is dissolved in ethyl acetate. The solution is washed with water and dried over magnesium sulphate. The solvent is removed and the residue is extracted several times with ether. The ether extract is diluted with 2 volumes of hexane. 1- (2-chloro-4-nitrobenzyl) -1H-imidazole (4.3 g) crystallizes to a white solid. 4 g of this material are mechanically stirred at reflux with 153 ml of methanol, 52 ml of water, 8.1 g of ammonium chloride and 6.6 g of iron powder for 2 hours. The hot mixture is filtered and the solids are washed with a hot methanol-tetrahydrofuran mixture. Solvent is removed from the combined filtrates. The residue is extracted several times with hot ethyl acetate. The ethyl acetate solution is treated with magnesium sulfate and activated with charcoal. Filter and remove the solvent to afford 3.9 g of the title compound.

Using the method described in Examples 1-179 above and the method described in patent applications WO-98 / 43960 and WO-99 / 09016, the compounds of the invention listed in Table 5 are prepared.

Example compound m.p. (° C) Mass spectrum 180 4- (2-hydroxy-naphthalen-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile 240 decomposition 371.9 (M + H) 181 4- (2,3-Dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile 200-201 364.0 (M + H) 182 4- (2-mercapto-benzothiazol-6-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile > 255 decomposition 394.8 (M + H) 183 4- (6-hydroxy-naphthalen-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile 205 Disassembly 372.0 (M + H) 184 4- (1H-indazol-6-ylamino) -5-methoxy-quinoline-3-carbonitrile > 260 315.8 (M + H) 185 4- (2-Chloro-5-methoxyanilino) -5-methoxyquinoline-3-carbonitrile 185-187 339.9 (M + H) 186 4-[(2-amino-4-chlorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile 215 Disassembly 354.9 (M + H) 187 4-[(3-hydroxy-2-naphthyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile 277-282 decomposition 372.2 (M + H) 188 4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile 467.2 (M + H)

Example compound m.p. (° C) Mass spectrum 189 6-amino-4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile 437.0 (M + H) 190 (E) -N- (4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -3-cyano-7-methoxy-6- Quinolinyl) -4- (dimethylamino) -2-buteneamide 548.1 (M + H), 274.7 (M + 2H) ⁺² 191 4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -7-methoxy-6-nitro-3-quinolinecarbonitrile 470.0 (M + H) 192 6-amino-4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -7-methoxy-3-quinolinecarbonitrile 440.1 (M + H) 193 (E) -N- {4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -3-cyano-7-methoxy-6-quinolinyl} -4- (dimethylamino) -2-buteneamide 551.1 (M + H) 276.2 (M + 2H) ⁺² 194 4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -7-methoxy-6-nitro-3-quinolinecarbonitrile 421.3 (M + H), 211.1 (M + 2H) ⁺² 195 6-amino-4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -7-methoxy-3-quinolinecarbonitrile 391.2 (M + H), 196.2 (M + 2H) ⁺² 196 (E) -N- {4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -3-cyano-7-methoxy-6-quinolinyl} -4- ( Dimethylamino) -2-buteneamide 502.4 (M + H), 251.7 (M + 2H) ⁺² 197 4- {3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile 531.2 (M + H), 266.2 (M + 2H) ⁺² 198 6-amino-4- {3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile 501.3 (M + H), 251.1 (M + 2H) ⁺² 199 (E) -N- (4- {3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -3-cyano-7-meth Methoxy-6-quinolinyl) -4- (dimethylamino-2-butenamide 612.4 (M + H), 306.7 (M + 2H) ⁺² 200 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (4-pyridinylmethyl) anilino] -3-quinolinecarbonitrile 139-141 510.2 (M + H), 255.7 (M + 2H) ⁺² 201 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-pyridinylmethyl) anilino] -3-quinolinecarbonitrile 112-114 510.3 (M + H), 255.7 (M + 2H) ⁺² 202 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-pyridinylmethyl) anilino] -3-quinolinecarbonitrile 168-170 510.2 (M + H), 255.7 (M + 2H) ⁺² 203 (E) -N- (4- {4- [acetyl (3-pyridinylmethyl) amino] -3-chloroanilino} -3-cyano-7-methoxy-6-quinolinyl) -4- (Dimethylamino) -2-buteneamide 584.1 (M + H), 292.7 (M + 2H) ⁺²

Example compound m.p. (° C) Mass spectrum 204 N- {2-chloro-4-[(3-cyano-7-methoxy-6-nitro-4-quinolinyl) amino] phenyl} -N- (3-pyridinylmethyl) acetamide 503.1 (M + H), 252.1 (M + 2H) ⁺² 205 N- {4-[(6-amino-3-cyano-7-methoxy-4-quinolinyl) amino] -2-chlorophenyl} -N- (3-pyridinylmethyl) acetamide 473.1 (M + H), 237.2 (M + 2H) ⁺² 206 N- (4-{[6- (acetylamino) -3-cyano-7-methoxy-4-quinolinyl] amino} -2-chlorophenyl) -N- (3-pyridinylmethyl) acetamide 515.1 (M + H) 207 4- [3-chloro-4- (1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrimidinyl) anilino] -7-methoxy-6-nitro-3-quinolinecarbo Nitrile 270-272 509.2 (M + H) 208 4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile 256-262 546.2 (M + H) 209 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-thienylmethyl) anilino] -3-quinolinecarbonitrile 152-153 515.3 (M + H), 258.3 (M + 2H) ⁺² 210 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-thienylmethyl) anilino] -3-quinolinecarbonitrile 152-154 515.3 (M + H), 258.3 (M + 2H) ⁺² 211 6-methoxy-4- (4-phenoxyanilino) -7- [2- (2H-1,2,3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile 154-155 479.3 (M + H) 212 6-methoxy-4- (4-phenoxyanilino) -7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile 188-189 479.3 (M + H) 213 4- (4-benzylanilino) -6-methoxy-7- [2- (2H-1,2,3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile 167-170 477.4 (M + H) 214 4- (4-benzylanilino) -6-methoxy-7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile 477.5 (M + H) 215 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-pyridinyloxy) anilino] -3-quinolinecarbonitrile 127-130 512.6 (M + H), 256.8 (M + 2H) ⁺² 216 4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) propoxy ] -3-quinolinecarbonitrile 234-235 565.4 (M + H), 283.5 (M + 2H) ⁺² 217 4- [4- (2-furylmethyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile 149-151 499.5 (M + H), 250.3 (M + 2H) ⁺² 218 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (tetrahydro-2-furanylmethyl) anilino] -3-quinolinecarbonitrile 132-134 503.4 (M + H), 252.4 (M + 2H) ⁺²

Example compound m.p. (° C) Mass spectrum 219 4- [4- (3-furylmethyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile 163-165 499.5 (M + H), 250.3 (M + 2H) ⁺² 220 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (tetrahydro-3-furanylmethyl) anilino] -3-quinolinecarbonitrile 123-125 503.4 (M + H), 252.2 (M + 2H) ⁺² 221 4- (3-chloro-4-{[5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino} anilino) -7-ethoxy-6-nitro-3 -Quinolinecarbonitrile 536.1 (M + H) 222 (E) -N- [4- (3-chloro-4-{[5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino} anilino) -3-sia No-7-ethoxy-6-quinolinyl] -4- (dimethylamino) -2-butenamide 617.3 (M + H), 309.3 (M + 2H) ⁺² 223 4- [3-chloro-4- (4-pyridinyloxy) anilino] -7-ethoxy-6-nitro-3-quinolinecarbonitrile 462.2 (M + H), 231.6 (M + 2H) ⁺² 224 6-amino-4- [3-chloro-4- (4-pyridinyloxy) anilino] -7-ethoxy-3-quinolinecarbonitrile 432.4 (M + H), 216.6 (M + 2H) ⁺² 225 (E) -N- {4- [3-chloro-4- (4-pyridinyloxy) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethylamino) -2-buteneamide 543.4 (M + H), 272.2 (M + 2H) ⁺² 226 4- {3-chloro-4-[(3-pyridinylmethyl) amino] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile 461.3 (M + H), 231.4 (M + 2H) ⁺² 227 6-amino-4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile 166-172 516.2 (M + H) 228 6-amino-4- (3-chloro-4-{[5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino} anilino) -7-ethoxy-3 -Quinolinecarbonitrile 506.3 (M + H) 229 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-phenylethyl) anilino] -3-quinolinecarbonitrile 106-108 523.5 (M + H), 262.4 (M + 2H) ⁺² 230 (E) -N- (4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -3-cyano-7-methoxy- 6-quinolinyl) -4- (dimethylamino) -2-butenamide 154-157 627.3 (M + H), 314.3 (M + 2H) ⁺² 231 4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile 130-133 519.3 (M + H), 260.3 (M + 2H) ⁺² 232 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-pyridinyloxy) anilino] -3-quinolinecarbonitrile 135-137 512.2 (M + H), 256.7 (M + 2H) ⁺²

Example compound m.p. (° C) Mass spectrum 233 4- [3-chloro-4- (4-pyridinyloxy) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile 174 Disassembly 546.1 (M + H), 273.8 (M + 2H) ⁺² 234 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (4-pyridinyloxy) anilino] -3-quinolinecarbonitrile 129-131 512.1 (M + H), 256.8 (M + 2H) ⁺² 235 4- [2-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3- Quinolinecarbonitrile 122 568.0 (M + H), 284.7 (M + 2H) ⁺² 236 N- [2-chloro-4-({3-cyano-6-methoxy-7- [3- (4-morpholinyl) propoxy] -4-quinolinyl} amino) phenyl] -N- (3-pyridinylmethyl) acetamide 120 decomposition 601.1 (M + H), 301.3 (M + 2H) ⁺² 237 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (1H-tetrazol-5-ylmethyl) anilino] -3-quinolinecarbonitrile 208 Disassembly 501.2 (M + H), 251.0 (M + 2H) ⁺² 238 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2H-1,2,3-triazol-2-ylmethyl) anilino] -3-quinoline Carbonitrile 186-187 500.3 (M + H), 250.8 (M + 2H) ⁺² 239 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (1H-1,2,3-triazol-1-ylmethyl) anilino] -3-quinoline Carbonitrile 200-201 500.2 (M + H), 250.7 (M + 2H) ⁺² 240 4- (2,4-Dichloro-5-methoxyanilino) -6-methoxy-7- [2- (2H-1,2,3-triazol-2-yl) ethoxy] -3-quinoline Carbonitrile 223-226 485.1 (M + H) 241 4- (2,4-Dichloro-5-methoxyanilino) -6-methoxy-7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3-quinoline Carbonitrile 196-197 485.1 (M + H) 242 7-ethoxy-6-nitro-4- [4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3-quinoline Carbonitrile 594.0 (M + H) 243 6-amino-7-ethoxy-4- [4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3-quinoline Carbonitrile 564.0 (M + H) 244 (E) -N- {3-cyano-7-ethoxy-4- [4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl ) Anilino] -6-quinolinyl} -4- (dimethylamino) -2-buteneamide 675.0 (M + H), 338.3 (M + 2H) ⁺² 245 4- [3-chloro-4- (1H-imidazol-1-ylmethyl) anilino] -7-ethoxy-6-nitro-3-quinolinecarbonitrile 449.1 (M + H), 225.2 (M + 2H) ⁺² 246 6-amino-4- [3-chloro-4- (1H-imidazol-1-ylmethyl) anilino] -7-ethoxy-3-quinolinecarbonitrile 419.2 (M + H), 210.3 (M + 2H) ⁺²

Example compound m.p. (° C) Mass spectrum 247 (E) -N- {4- [3-chloro-4- (1H-imidazol-1-ylmethyl) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (Dimethylamino) -2-buteneamide 530.2 (M + H), 265.8 (M + 2H) ⁺² 248 4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-6-nitro-3-quinolinecarbonitrile 493.0 (M + H) 249 6-amino-4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-3-quinolinecarbonitrile 463.1 (M + H) 250 (E) -N- (4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -3-cyano-7-ethoxy-6-quinolinyl ) -4- (dimethylamino) -2-buteneamide 574.1 (M + H), 287.8 (M + 2H) ⁺² 251 4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-6-nitro-3-quinolinecarbonitrile 507.1 (M + H) 252 6-amino-4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-3-quinolinecarbonitrile 477.1 (M + H) 253 (E) -N- (4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -3-cyano-7-ethoxy-6-qui Nolinyl) -4- (dimethylamino) -2-buteneamide 588.1 (M + H), 294.8 (M + 2H) ⁺² 254 4- [4- (1H-imidazol-2-ylmethyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile 156-158 499.3 (M + H), 250.3 (M + 2H) ⁺² 255 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (1H-tetrazol-1-ylmethyl) anilino] -3-quinolinecarbonitrile 180 Disassembly 501.3 (M + H), 251.3 (M + 2H) ⁺² 256 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2H-tetrazol-2-ylmethyl) anilino] -3-quinolinecarbonitrile 123 Disassembly 501.2 (M + H), 251.3 (M + 2H) ⁺² 257 4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) propoxy] 3-quinolinecarbonitrile 110-113 591.1 (M + H), 296.2 (M + 2H) ⁺² 258 4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3 -Quinolinecarbonitrile 10-113 577.1 (M + H), 289.2 (M + 2H) ⁺² , 577.1 (M + H), 289.2 (M + 2H) ⁺² 259 (E) -N- [4- (3-chloro-4-{[2- (phenylsulfanyl) acetyl] amino} anilino) -3-cyano-7-methoxy-6-quinolinyl]- 4- (dimethylamino) -2-buteneamide 194-198 601.3 (M + H), 301.1 (M + 2H) ⁺² 260 4- [4- (2,6-dimethoxyphenoxy) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile 160-162 571.4 (M + H)

Example compound m.p. (° C) Mass spectrum 261 6-methoxy-4- [4- (3-methoxyphenoxy) anilino] -7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile 132-134 541.5 (M + H) 262 6-methoxy-4- {4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -7- [3- (4-morpholinyl) propoxy] -3- Quinolinecarbonitrile 208-210 531.4 (M + H) 263 (E) -N- {4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -3-cyano-7-methoxy-6-quinolinyl} -4-[(2-methoxyethyl) (methyl) amino] -2-butenamide 595.1 (M + H), 298.1 (M + 2H) ⁺² 264 (E) -N- (4- {3-chloro-4-[(5-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -3-cyano-7-methoxy- 6-quinolinyl) -4- (dimethylamino) -2-butenamide 627.1 (M + H), 314.1 (M + 2H) ⁺² 265 (E) -N- (4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -3-cyano-7-ethoxy- 6-quinolinyl) -4- (dimethylamino) -2-butenamide 641.3 (M + H), 321.2 (M + 2H) ⁺² 266 4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -6,7-dimethoxy-3-quinolinecarbonitrile 173-176 478.4 (M + H) 267 6,7-dimethoxy-4-({6-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3-pyridinyl} amino) -3-quinolinecarbonitrile 250 (decomposition) 498.3 (M + H) 268 4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -6-methoxy-7- [3- (2H-1,2,3- Triazol-2-yl) propoxy] -3-quinolinecarbonitrile 232-234 547.3 (M + H) 269 4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -6-methoxy-7- [3- (1H-1,2,3- Triazol-1-yl) propoxy] -3-quinolinecarbonitrile 208-210 547.3 (M + H)

Claims (16)

A compound of formula 1 or a pharmaceutically acceptable salt thereof. Formula 1 In the above formula, X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, and the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O and S, provided that acyclic hetero The aryl ring does not contain OO, SS or SO bonds, and the bicyclic aryl or bicyclic heteroaryl rings are halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, 2 Alkynyl of 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1- Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, carbo of 2-7 carbon atoms Alkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbons Of alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, of 3-8 carbon atoms Alkinoylamino, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, 3 -N, N-dialkylaminoalkyl of 10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy, mercapto and benzoylamino of 3-10 carbon atoms Optionally mono-, di-, tri- or tetra-substituted with a substituent selected from the group consisting of: X is a chemical formula Radicals wherein A is a pyridinyl, pyrimidinyl or phenyl ring; a pyridinyl, pyrimidinyl or phenyl ring is halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, Alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1 Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, of 2-7 carbon atoms Carboalkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, 1-6 Alkanoylamino of carbon atom, Alkenoylamino of 3-8 carbon atoms, Alkynoylamino of 3-8 carbon atoms, 2-7 carbons Carboxyalkyl of atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N- of 3-10 carbon atoms Optionally mono- or substituted with a substituent selected from the group consisting of dialkylaminoalkyl, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino Di-substituted; T is bonded to the carbon of A and -NH (CH ₂ ) _m- , -O (CH ₂ ) _m- , -S (CH ₂ ) _m- , -NR (CH ₂ ) _m -,-(CH ₂ ) _m -,-(CH ₂ ) _m NH-,-(CH ₂ ) _m O-,-(CH ₂ ) _m S- or-(CH ₂ ) _m NR-; L is an unsubstituted phenyl ring or halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxy of 1-6 carbon atoms Alkyl, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, tri of 1-6 carbon atoms Fluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 Alkylamino of 2 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, 3-8 Alkynylamino of carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N of 3-10 carbon atoms , Is a phenyl ring mono-, di- or tri-substituted with a substituent selected from the group consisting of N-dialkylaminoalkoxy, mercapto and benzoylamino; Provided that L can be an unsubstituted phenyl ring only when m> 0 and T is not -CH ₂ NH- or -CH ₂ O-; L is a 5 or 6 membered heteroaryl ring, wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O and S, provided that the heteroaryl ring contains no OO, SS or SO bonds and the heteroaryl ring is Halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halo Methyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, trifluoromethyl of 1-6 carbon atoms , Cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbon atoms Alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkano of 1-6 carbon atoms Amino, alkenoylamino of 3-8 carbon atoms, alkinoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, 1-5 Aminoalkyl of carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, 3- Optionally mono- or di-substituted with a substituent selected from the group consisting of 10 carbon atoms of N, N-dialkylaminoalkoxy, mercapto and benzoylamino; Z is -NH-, -O-, -S- or -NR-; R is alkyl of 1-6 carbon atoms or carboalkyl of 2-7 carbon atoms; G ₁ , G ₂ , R ₁ and R ₄ are each independently hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, 2-6 Alkenyloxy of 2 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, 3- Alkynoyloxy of 8 carbon atoms, Alkanoyloxymethyl of 2-7 carbon atoms, Alkenoyloxymethyl of 4-9 carbon atoms, Alkynoyloxymethyl of 4-9 carbon atoms, 2-7 Alkoxymethyl of 1 carbon atom, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, 1- Alkylsulfonamido of 6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cya Rowing, Tro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxy of 1-4 carbon atoms Amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N of 4 to 12 carbon atoms Alkenylamino, N, N-dialkenylamino, phenylamino, benzylamino of 6-12 carbon atoms, Or; R ₁ and R ₄ are as described above and G ₁ or G ₂ or both are R ₂ -NH-; If the substituents R ₁ , G ₂ , G ₃ or R ₄ are located on adjacent carbon atoms they can be taken together as a _divalent radical -OC (R ₆ ) ₂ -O-; Y is A divalent radical selected from the group consisting of; R ₇ is —NR ₆ R ₆ , —OR ₆ , —J, —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ); M is> NR ₆ , -O-,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p -OR ₆ ; W is> NR ₆ , -O- or a bond; Het is morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S, S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran and It is selected from the group consisting of; Wherein Het is optionally mono- or di-substituted with R ₆ on carbon or nitrogen, hydroxy on carbon, —N (R ₆ ) ₂ or Optionally mono- or di-substituted with -OR ₆ and optionally mono with monovalent radicals-(C (R ₆ ) ₂ ) _s OR ₆ or-(C (R ₆ ) ₂ ) _s N (R ₆ ) ₂ on carbon Or di-substituted and optionally mono or di-substituted with a divalent radical —O— or —O (C (R ₆ ) ₂ ) _s O— on saturated carbon; R ₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, of 2-7 carbon atoms Carboalkyl, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms , Dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1-6 carbons Alkylthio, hydroxy, carboxyl of atoms, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms Or alkyl of 1-6 carbon atoms: provided that the alkenyl or alkynyl moiety is via a saturated carbon atom a nitrogen or oxygen atom And the sum; R ₂ is selected from the group consisting of: R ₃ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₅ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₈ and R ₉ are, independently from each other, — (C (R ₆ ) ₂ ) _r NR ₆ R ₆ or — (C (R ₆ ) ₂ ) _r OR ₆ ; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl or hydrogen of 1-6 carbon atoms; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; m is 0-3; p = 2-4; q = 0-4; r = 1-4; s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; Provided that if R ₆ is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, these alkenyl or alkynyl moieties are bonded to nitrogen or oxygen atoms via saturated carbon atoms; Further, if Y is —NR ₆ — and R ₇ is —NR ₆ R ₆ , —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ), g = 2-6; When M is -O- and R ₇ is -OR _6, p = 1-4; If Y is —NR ₆ — then k = 2-4; When Y is -O- and M or W is -O-, k = 1-4; Q = 2-4 unless W is a bond to Het bonded via a nitrogen atom; If W is a bond to Het bonded through a nitrogen atom and Y is -O- or -NR ₆ -then k = 2-4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is -NH- and n = 0. 3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein X is a substituted or unsubstituted bicyclic aryl or bicyclic heteroaryl ring system. 3. A compound according to claim 2 wherein X is a radical And A is a phenyl ring or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₄ are hydrogen. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R ₁ and R ₄ are hydrogen. 4. The bicyclic aryl or bicyclic heteroaryl ring system of claim 3, wherein the bicyclic aryl or bicyclic heteroaryl ring system is selected from naphthalin, 1,2,3,4-tetrahydronaphthalin, indane, 1-oxo-indane, 1,2,3,4 Tetrahydroquinoline, naphthyridine, benzofuran, 3-oxo-1,3-dihydro-isobenzofuran, benzothiaphene, 1,1-dioxo-benzothiaphene, indole, 2,3-dihydroindole , 1,3-dioxo-2,3-dihydro-1H-isoindole, benzotriazole, 1H-indazole, indolin, benzopyrazole, 1,3-benzodioxol, benzoxazole, purine, Phthalimide, coumarin, chromone, quinoline, terahydroquinoline, isoquinoline, benzimidazole, quinazoline, pyrido [2,3-b] pyridine, pyrido [3,4-b] pyrazine, pyrido [ 3,2-c] pyridazine, pyrido [3,4-b] pyridine, 1H-pyrazole [3,4-d] pyrimidine, 1,4-benzodioxane, pteridine, 2 (1H) -Quinolone, 1 (2H) -isoquinolone, 2-oxo-2,3-dihydro-benzthiazole, 1,2-methylenedioxybenzene, 2-oxindole, 1,4-benz Photograph, benzothiazole, quinoxaline, quinoline-N-oxide, isoquinoline-N-oxide, quinoxaline-N-oxide, quinazoline-N-oxide, benzoazine, phthalazine, 1,4-dioxo -1,2,3,4-tetrahydro-phthalazine, 2-oxo-1,2-dihydro-quinoline, 2,4-dioxo-1,4-dihydro-2H-benzo [d] [ 1,3] oxazine, 2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [e] [1,4] -diazepine and cinnoline; or Pharmaceutically acceptable salts thereof. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein L is a 5- or 6-membered heteroaryl ring. The compound according to claim 8, wherein the heteroaryl ring is selected from the group consisting of pyridine, pyrimidine, imidazole, thiazole, thiazolidine, pyrrole, furan, thiophene, oxazole and 1,2,4-triazole or Pharmaceutically acceptable salts. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein L is a substituted phenyl ring. The method of claim 1, a) 4- (2,3-dihydro-1H-indol-6-ylamino) -6,7-diethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; b) 4- (benzothiazol-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; c) 4- (benzo [1,3] dioxol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; d) 6,7-diethoxy-4- (1H-indazol-6-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; e) 6,7-diethoxy-4- (4-methyl-2-oxo-2H-chromen-7-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; f) 6,7-diethoxy-4- (1H-indol-6-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; g) 6,7-dimethoxy-4- (1H-indazol-6-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; h) 4- (1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable thereof salt; i) 4- (2,3-dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; j) 4- (1H-indazol-6-ylamino) -6,7-bis- (2-methoxy-ethoxy) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; k) 4- (1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutical thereof Salts acceptable; l) 6,7-diethoxy-4- (indan-5-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; m) 4- (2,4-dioxo-1,4-dihydro-2H-benzo [d] [1,3] oxazin-6-ylamino) -6,7-diethoxy-quinoline-3- Carbonitrile or a pharmaceutically acceptable salt thereof; n) 6,7-diethoxy-4- (3-oxo-1,3-dihydro-isobenzofuran-5-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; o) 4- (1,1-dioxo-1H-benzo [b] thiophen-6-ylamino) -6,7-diethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; p) 4- (2,3-dihydro-1H-indol-6-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; q) 7-ethoxy-4- (indazol-6-ylamino) -6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; r) 4- (2,3-dihydro-1H-indol-6-ylamino) -6-methoxy-7- (3-pyridin-4-yl-propoxy) -quinoline-3-carbonitrile or its Pharmaceutically acceptable salts; s) 9- (1H-indazol-6-ylamino) -2,3-dihydro [1,4] dioxino [2,3-g] quinoline-8-carbonitrile or a pharmaceutically acceptable thereof salt; t) 6,7-diethoxy-4- (1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [e] [1,4] diazepine-7- Monoamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; u) 4- (1H-indazol-6-ylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; v) 6,7-dimethoxy-4- (4-methyl-2-oxo-1,2-dihydro-quinolin-7-ylamino) -quinoline-3-carbonitrile; w) 6,7-dimethoxy-4- (2-methyl-benzothiazol-5-ylamino) -quinoline-3-carbonitrile x) 6,7-dimethoxy-4- (2-oxo-2,3-dihydro-benzothiazol-6-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; y) 6,7-dimethoxy-4- (quinolin-5-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; z) 4- (isoquinolin-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; aa) 6,7-dimethoxy-4- (quinolin-8-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; bb) 4- (8-hydroxy-quinolin-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; cc) 4- (1H-indol-4-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; dd) 4- (1H-indazol-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; ee) 4- (1H-indazol-6-ylamino) -5,8-dimethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; ff) 4- (1H-indazol-6-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile or a pharmaceutically acceptable thereof salt; gg) 4- (3H-benzotriazol-5-ylamino) -7-methoxy-6- (3-morpholin-4-yl-propoxy) -quinoline-3-carbonitrile or a pharmaceutically acceptable thereof Salts; hh) 4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ii) 4- (3H-benzotriazol-5-ylamino) -6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; jj) 4- (1H-indazol-6-ylamino) -7-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; kk) 4- (3H-benzotriazol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ll) 7-hydroxy-4- (1H-indazol-6-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; mm) 4- (1H-indol-5-ylamino) -7-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; nn) 7-hydroxy-4- (3H-benzotrizol-5-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; oo) 4- (1H-indazol-6-ylamino) -8-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; pp) 4- (3H-benzotriazol-5-ylamino) -8-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; qq) 4- (1H-indol-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; rr) 4- (1H-benzoimidazol-5-ylamino) -6,7-dimethoxy-quinolin-3-carbonitrile or a pharmaceutically acceptable salt thereof; ss) 6,7-dimethoxy-4- (2-methyl-1H-benzoimidazol-5-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; tt) 6,7-dimethoxy-4- (quinolin-6-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; uu) 4- (4-chloro-naphthalen-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; vv) 6,7-dimethoxy-4- (5,6,7,8-tetrahydro-naphthalen-1-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ww) 4- (3H-benzotriazol-5-ylamino) -6,7,8-trimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; xx) 4- (1H-indazol-6-ylamino) -6-methoxy-7- [2- (4-methyl-piperazin-1-yl) -ethoxy] -quinoline-3-carbonitrile or Pharmaceutically acceptable salts thereof; yy) 7- {2-[(2-hydroxy-ethyl) -amino] -ethoxy} -4 (1H-indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or its Pharmaceutically acceptable salts; zz) 7- {2- [bis- (2-hydroxy-ethyl) -amino] -ethoxy} -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline-3-carbo Nitrile or a pharmaceutically acceptable salt thereof; aaa) 7- [2- (4-hydroxy-piperidin-1-yl) -ethoxy] -4- (indazol-6-ylamino) -6-methoxy-quinoline-3-carbonitrile or Pharmaceutically acceptable salts thereof; bbb) 7- {2-[(4- (2-hydroxy-ethyl) -piperazin-1-yl) -ethoxy] -4- (1H-indazol-6-ylamino) -6-methoxy -Quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ccc) 7- [2- (1, 4-dioxa-8-aza-spiro [4,5] dec-8-yl) -ethoxy] -4- (1H-indazol-6-ylamino) 6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ddd) 7- [2-([1,3] dioxolan-2-ylmethyl-methyl-amino) -ethoxy] -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline -3-carbonitrile; eee) 7- [2- (3,4-dihydro-1H-isoquinolin-2-yl) -ethoxy] -4- (1H-indazol-6-ylamino) -6-methoxy-quinoline- 3-carbonitrile or a pharmaceutically acceptable salt thereof; fff) 4- (1H-indazol-6-ylamino) -6-methoxy-7- (2-thiomorpholin-4-yl-ethoxy) -quinoline-3-carbonitrile or a pharmaceutically acceptable thereof Salts; ggg) 7- (2-chloroethoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; hhh) 7- (2-dimethylaminoethoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; iii) 4- (1H-indazol-6-ylamino) -6-methoxy-7- (2-morpholin-4-yl-ethoxy) quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof ; jjj) 4- (3H-benzotriazol-5-ylamino) -7- (2-chloroethoxy) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; kkk) 7- (3-chloropropoxy) -4- (1H-indazol-6-ylamino) -6-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; lll) 4- (1H-indazol-6-ylamino) -6-methoxy-7- (3-morpholin-4-ylpropoxy) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof ; mmm) 4- [3-chloro-4- (1-methyl-2-imidazolylthio) phenylamino] -6,7-diethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; nnn) 4- [3-chloro-4- (1-methyl-2-imidazolylthio) phenylamino] -6,7-dimethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ooo) 6-amino-4- [3-chloro-4- (1-methyl-1H-imidazol-2-ylsulfanyl) -phenylamino] -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof ; ppp) N- {4- [3-chloro-4- (1-methyl-1H-imidazol-2-ylsulfanyl) -phenylamino] -3-cyano-quinolin-6-yl} -acrylamide or Pharmaceutically acceptable salts thereof; qqq) 6-amino-4- (1H-indol-5-ylamino) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; rrr) 4- (1H-indol-5-ylamino) -6-nitro-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; sss) 4- (2-hydroxy-naphthalen-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; ttt) 4- (2,3-dihydro-benzo [1,4] dioxin-6-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; uuu) (2-mercapto-benzothiazol-6-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; vvv) 4- (6-hydroxy-naphthalen-1-ylamino) -6,7-dimethoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; www) 4- (1H-indazol-6-ylamino) -5-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; xxx) 4- (2-chloro-5-methoxyanilino) -5-methoxyquinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof; yyy) 4-[(2-amino-4-chlorophenyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; zzz) 4-[(3-hydroxy-2-naphthyl) amino] -6,7-dimethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; aaaa) 4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; bbbb) 6-amino-4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; cccc) (E) -N- (4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -3-cyano-7-methoxy- 6-quinolinyl) -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; dddd) 4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable thereof salt; eeee) 6-amino-4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable thereof salt; ffff) (E) -N- {4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -3-cyano-7-methoxy-6-quinoli Nil} -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; gggg) 4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; hhhh) 6-amino-4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -7-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; iiii) (E) -N- {4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -3-cyano-7-methoxy-6-quinolinyl} -4 -(Dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; jjjj) 4- {3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbo Nitrile or a pharmaceutically acceptable salt thereof; kkkk) 6-amino-4- {3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbo Nitrile or a pharmaceutically acceptable salt thereof; llll) (E) -N- (4- {3-chloro-4-[(4-oxo-3,4-dihydro-2-quinazolinyl) sulfanyl] anilino} -3-cyano-7 -Methoxy-6-quinolinyl) -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; mmmm) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (4-pyridinylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; nnnn) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-pyridinylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; oooo) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-pyridinylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; pppp) (E) -N- (4- {4- [acetyl (3-pyridinylmethyl) amino] -3-chloroanilino} -3-cyano-7-methoxy-6-quinolinyl)- 4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; qqqq) N- {2-chloro-4-[(3-cyano-7-methoxy-6-nitro-4-quinolinyl) amino] phenyl} -N- (3-pyridinylmethyl) acetamide or Pharmaceutically acceptable salts thereof; rrrr) N- {4-[(6-amino-3-cyano-7-methoxy-4-quinolinyl) amino] -2-chlorophenyl} -N- (3-pyridinylmethyl) acetamide or Pharmaceutically acceptable salts thereof; ssss) N- (4-{[6- (acetylamino) -3-cyano-7-methoxy-4-quinolinyl] amino} -2-chlorophenyl) -N- (3-pyridinylmethyl) Acetamide or a pharmaceutically acceptable salt thereof; tttt) 4- [3-chloro-4- (1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrimidinyl) anilino] -7-methoxy-6-nitro-3- Quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; uuuu) 4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile or Pharmaceutically acceptable salts thereof; vvvv) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-thienylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; wwww) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-thienylmethyl) -anilino] -3-quinolinecarbonitrile or a pharmaceutical thereof Acceptable salts; xxxx) 6-methoxy-4- (4-phenoxyanilino) -7- [2- (2H-1,2,3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile or its Pharmaceutically acceptable salts; yyyy) 6-methoxy-4- (4-phenoxyanilino) -7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile or its Pharmaceutically acceptable salts; zzzz) 4- (4-benzylanilino) -6-methoxy-7- [2- (2H-1,2,3-triazol-2-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; aaaaa) 4- (4-benzylanilino) -6-methoxy-7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; bbbbb) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-pyridinyloxy) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; ccccc) 4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) Propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ddddd) 4- [4- (2-furylmethyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof salt; eeeee) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (tetrahydro-2-furanylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; fffff) 4- [4- (3-furylmethyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof salt; ggggg) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (tetrahydro-3-furanylmethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; hhhhh) 4- (3-chloro-4-{[5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino} anilino) -7-ethoxy-6-nitro -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; iiiii) (E) -N- [4- (3-chloro-4-{[5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino} anilino) -3 -Cyano-7-ethoxy-6-quinolinyl] -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; jjjjj) 4- [3-chloro-4- (4-pyridinyloxy) anilino] -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; kkkkk) 6-amino-4- [3-chloro-4- (4-pyridinyloxy) anilino] -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; lllll) (E) -N- {4- [3-chloro-4- (4-pyridinyloxy) anilino] -3-cyano-7-ethoxy-6-quinolinyl} -4- (dimethyl Amino) -2-buteneamide or a pharmaceutically acceptable salt thereof; mmmmm) 4- {3-chloro-4-[(3-pyridinylmethyl) amino] anilino} -7-methoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; nnnnn) 6-amino-4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -7-methoxy-3-quinolinecarbonitrile or Pharmaceutically acceptable salts thereof; ooooo) 6-amino-4- (3-chloro-4-{[5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] amino} anilino) -7-ethoxy -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ppppp) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2-phenylethyl) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof salt; qqqqq) (E) -N- (4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -3-cyano-7-meth Methoxy-6-quinolinyl) -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; rrrrr) 4- [3-chloro-4- (1H-imidazol-1-yl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbo Nitrile or a pharmaceutically acceptable salt thereof; sssss) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (3-pyridinyloxy) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; ttttt) 4- [3-chloro-4- (4-pyridinyloxy) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or its Pharmaceutically acceptable salts; uuuuu) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (4-pyridinyloxy) anilino] -3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; vvvvv) 4- [2-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy]- 3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; wwwww) N- [2-chloro-4-({3-cyano-6-methoxy-7- [3- (4-morpholinyl) propoxy] -4-quinolinyl} amino) phenyl]- N- (3-pyridinylmethyl) acetamide or a pharmaceutically acceptable salt thereof; xxxxx) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (1H-tetrazol-5-ylmethyl) anilino] -3-quinolinecarbonitrile or its Pharmaceutically acceptable salts; yyyyy) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2H-1,2,3-triazol-2-ylmethyl) anilino] -3 Quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; zzzzz) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (1H-1,2,3-triazol-1-ylmethyl) anilino] -3 Quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; aaaaaa) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [2- (2H-1,2,3-triazol-2-yl) ethoxy] -3 Quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; bbbbbb) 4- (2,4-dichloro-5-methoxyanilino) -6-methoxy-7- [2- (1H-1,2,3-triazol-1-yl) ethoxy] -3 Quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; cccccc) 7-ethoxy-6-nitro-4- [4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3 Quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; dddddd) 6-amino-7-ethoxy-4- [4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoromethyl) anilino] -3 Quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; eeeeee) (E) -N- {3-cyano-7-ethoxy-4- [4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3- (trifluoro Romethyl) anilino] -6-quinolinyl} -4- (dimethylamino) -2-butenamide or a pharmaceutically acceptable salt thereof; ffffff) 4- [3-chloro-4- (1H-imidazol-1-ylmethyl) anilino] -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; gggggg) 6-amino-4- [3-chloro-4- (1H-imidazol-1-ylmethyl) anilino] -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; hhhhhh) (E) -N- {4- [3-chloro-4- (1H-imidazol-1-ylmethyl) anilino] -3-cyano-7-ethoxy-6-quinolinyl}- 4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; iiiiii) 4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; jjjjjj) 6-amino-4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable thereof Salts; kkkkkk) (E) -N- (4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -3-cyano-7-ethoxy-6-qui Nolinyl) -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; llllll) 4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-6-nitro-3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; mmmmmm) 6-amino-4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -7-ethoxy-3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; nnnnnn) (E) -N- (4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -3-cyano-7-ethoxy-6 -Quinolinyl) -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; oooooo) 4- [4- (1H-imidazol-2-ylmethyl) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or its Pharmaceutically acceptable salts; pppppp) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (1H-tetrazol-1-ylmethyl) anilino] -3-quinolinecarbonitrile or its Pharmaceutically acceptable salts; qqqqqq) 6-methoxy-7- [3- (4-morpholinyl) propoxy] -4- [4- (2H-tetrazol-2-ylmethyl) anilino] -3-quinolinecarbonitrile or its Pharmaceutically acceptable salts; rrrrrr) 4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -6-methoxy-7- [3- (4-morpholinyl) prop Foxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; ssssss) 4- {3-chloro-4-[(4-methyl-2-pyrimidinyl) sulfanyl] anilino} -6-methoxy-7- [30 (4-morpholinyl) propoxy]- 3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; tttttt) (E) -N- [4- (3-chloro-4-{[2- (phenylsulfanyl) acetyl] amino} anilino) -3-cyano-7-methoxy-6-quinolinyl ] -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; uuuuuu) 4- [4- (2,6-dimethoxyphenoxy) anilino] -6-methoxy-7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutical thereof Salts acceptable; vvvvvv) 6-methoxy-4- [4- (3-methoxyphenoxy) anilino] -7- [3- (4-morpholinyl) propoxy] -3-quinolinecarbonitrile or a pharmaceutical thereof Acceptable salts; wwwwww) 6-methoxy-4- {4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -7- [3- (4-morpholinyl) propoxy]- 3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; xxxxxx) (E) -N- {4- [3-chloro-4- (1,3-thiazol-2-ylsulfanyl) anilino] -3-cyano-7-methoxy-6-quinoli Nil} -4-[(2-methoxyethyl) (methyl) amino] -2-buteneamide or a pharmaceutically acceptable salt thereof; yyyyyy) (E) -N- (4- {3-chloro-4-[(5-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -3-cyano-7-meth Methoxy-6-quinolinyl) -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; zzzzzz) to (E) -N- (4- {3-chloro-4-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] anilino} -3-cyano-7- Methoxy-6-quinolinyl) -4- (dimethylamino) -2-buteneamide or a pharmaceutically acceptable salt thereof; (aaaaaaa) 4- {3-chloro-4-[(4,6-dimethyl-2-pyrimidinyl) sulfanyl] anilino} -6,7-dimethoxy-3-quinolinecarbonitrile or a pharmaceutical thereof Acceptable salts; bbbbbbb) 6,7-dimethoxy-4-({6-[(4-phenyl-1,3-thiazol-2-yl) sulfanyl] -3-pyridinyl} amino) -3-quinolinecarbonitrile or Pharmaceutically acceptable salts thereof; or ccccccc) 4- {3-chloro-4-[(1-methyl-1H-imidazol-2-yl) sulfanyl] anilino} -6-methoxy-7- [3- (1H-1,2, 3-triazol-1-yl) propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof. A method of treating, inhibiting growth or eradicating a neoplasm in a mammal in need thereof comprising administering to the mammal an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Formula 1 In the above formula, X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, and the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O and S, provided that acyclic hetero The aryl ring does not contain OO, SS or SO bonds, and the bicyclic aryl or bicyclic heteroaryl ring is halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, 2 Alkynyl of 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1- Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, carbo of 2-7 carbon atoms Alkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbon sources Of alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, of 3-8 carbon atoms Alkinoylamino, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, 3 -N, N-dialkylaminoalkyl of 10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy, mercapto and benzoylamino of 3-10 carbon atoms Optionally mono-, di-, tri- or tetra-substituted with a substituent selected from the group consisting of: X is a chemical formula Radicals wherein A is a pyridinyl, pyrimidinyl or phenyl ring; a pyridinyl, pyrimidinyl or phenyl ring is halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, Alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1 Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, of 2-7 carbon atoms Carboalkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, 1-6 Alkanoylamino of carbon atom, Alkenoylamino of 3-8 carbon atoms, Alkynoylamino of 3-8 carbon atoms, 2-7 carbons Carboxyalkyl of atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N- of 3-10 carbon atoms Optionally mono- or substituted with a substituent selected from the group consisting of dialkylaminoalkyl, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino Di-substituted; T is bonded to the carbon of A and -NH (CH ₂ ) _m- , -O (CH ₂ ) _m- , -S (CH ₂ ) _m- , -NR (CH ₂ ) _m -,-(CH ₂ ) _m -,-(CH ₂ ) _m NH-,-(CH ₂ ) _m O-,-(CH ₂ ) _m S- or-(CH ₂ ) _m NR-; L is an unsubstituted phenyl ring or halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxy of 1-6 carbon atoms Alkyl, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, tri of 1-6 carbon atoms Fluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 Alkylamino of 2 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, 3-8 Alkynylamino of carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N of 3-10 carbon atoms , Is a phenyl ring mono-, di- or tri-substituted with a substituent selected from the group consisting of N-dialkylaminoalkoxy, mercapto and benzoylamino; Provided that L can be an unsubstituted phenyl ring only when m> 0 and T is not -CH ₂ NH- or -CH ₂ O-; L is a 5 or 6 membered heteroaryl ring, wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O and S, provided that the heteroaryl ring contains no OO, SS or SO bonds and the heteroaryl ring is Halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halo Methyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, trifluoromethyl of 1-6 carbon atoms , Cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbon atoms Alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkano of 1-6 carbon atoms Amino, alkenoylamino of 3-8 carbon atoms, alkinoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, 1-5 Aminoalkyl of carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, 3- Optionally mono- or di-substituted with a substituent selected from the group consisting of 10 carbon atoms of N, N-dialkylaminoalkoxy, mercapto and benzoylamino; Z is -NH-, -O-, -S- or -NR-; R is alkyl of 1-6 carbon atoms or carboalkyl of 2-7 carbon atoms; G ₁ , G ₂ , R ₁ and R ₄ are each independently hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, 2-6 Alkenyloxy of 2 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, 3- Alkynoyloxy of 8 carbon atoms, Alkanoyloxymethyl of 2-7 carbon atoms, Alkenoyloxymethyl of 4-9 carbon atoms, Alkynoyloxymethyl of 4-9 carbon atoms, 2-7 Alkoxymethyl of 1 carbon atom, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, 1- Alkylsulfonamido of 6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cya Rowing, Tro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxy of 1-4 carbon atoms Amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N of 4 to 12 carbon atoms Alkenylamino, N, N-dialkenylamino, phenylamino, benzylamino of 6-12 carbon atoms, Or; R ₁ and R ₄ are as described above and G ₁ or G ₂ or both are R ₂ -NH-; If the substituents R ₁ , G ₂ , G ₃ or R ₄ are located on adjacent carbon atoms they can be taken together as a _divalent radical -OC (R ₆ ) ₂ -O-; Y is A divalent radical selected from the group consisting of; R ₇ is —NR ₆ R ₆ , —OR ₆ , —J, —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ); M is> NR ₆ , -O-,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p -OR ₆ ; W is> NR ₆ , -O- or a bond; Het is morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S, S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran and It is selected from the group consisting of; Wherein Het is optionally mono- or di-substituted with R ₆ on carbon or nitrogen, hydroxy on carbon, —N (R ₆ ) ₂ or Optionally mono- or di-substituted with -OR ₆ and optionally mono with monovalent radicals-(C (R ₆ ) ₂ ) _s OR ₆ or-(C (R ₆ ) ₂ ) _s N (R ₆ ) ₂ on carbon Or di-substituted and optionally mono or di-substituted with a divalent radical —O— or —O (C (R ₆ ) ₂ ) _s O— on saturated carbon; R ₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, 2-7 carbon atoms Carboalkyl, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkyl of 1-3 carbon atoms Amino, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1-6 Alkylthio, hydroxy, carboxyl of carbon atoms, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoyl of 1-6 carbon atoms Amino or alkyl of 1-6 carbon atoms, provided that alkenyl or alkynyl moieties are provided with nitrogen or oxygen atoms via saturated carbon atoms. And the sum; R ₂ is selected from the group consisting of: R ₃ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₅ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₈ and R ₉ are, independently from each other, — (C (R ₆ ) ₂ ) _r NR ₆ R ₆ or — (C (R ₆ ) ₂ ) _r OR ₆ ; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl or hydrogen of 1-6 carbon atoms; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; m is 0-3; p = 2-4; q = 0-4; r = 1-4; s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; Provided that if R ₆ is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, these alkenyl or alkynyl moieties are bonded to nitrogen or oxygen atoms via saturated carbon atoms; Further, if Y is —NR ₆ — and R ₇ is —NR ₆ R ₆ , —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ), g = 2-6; When M is -O- and R ₇ is -OR _6, p = 1-4; If Y is —NR ₆ — then k = 2-4; When Y is -O- and M or W is -O-, k = 1-4; Q = 2-4 unless W is a bond to Het bonded via a nitrogen atom; If W is a bond to Het bonded through a nitrogen atom and Y is -O- or -NR ₆ -then k = 2-4. The method of claim 12, wherein the neoplasm is selected from the group consisting of breast, kidney, bladder, oral cavity, larynx, airway, stomach, colon, ovary and lung. A method of treating, inhibiting, or eradicating cysticosin in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof. Formula 1 In the above formula, X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, and the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O and S, provided that acyclic hetero The aryl ring does not contain OO, SS or SO bonds, and the bicyclic aryl or bicyclic heteroaryl rings are halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, 2 Alkynyl of 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1- Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, carbo of 2-7 carbon atoms Alkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbons Of alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, of 3-8 carbon atoms Alkinoylamino, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, 3 -N, N-dialkylaminoalkyl of 10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy, mercapto and benzoylamino of 3-10 carbon atoms Optionally mono-, di-, tri- or tetra-substituted with a substituent selected from the group consisting of: X is a chemical formula Radicals wherein A is a pyridinyl, pyrimidinyl or phenyl ring; a pyridinyl, pyrimidinyl or phenyl ring is halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, Alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1 Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, of 2-7 carbon atoms Carboalkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, 1-6 Alkanoylamino of carbon atom, Alkenoylamino of 3-8 carbon atoms, Alkynoylamino of 3-8 carbon atoms, 2-7 carbons Carboxyalkyl of atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N- of 3-10 carbon atoms Optionally mono- or substituted with a substituent selected from the group consisting of dialkylaminoalkyl, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino Di-substituted; T is bonded to the carbon of A and -NH (CH ₂ ) _m- , -O (CH ₂ ) _m- , -S (CH ₂ ) _m- , -NR (CH ₂ ) _m -,-(CH ₂ ) _m -,-(CH ₂ ) _m NH-,-(CH ₂ ) _m O-,-(CH ₂ ) _m S- or-(CH ₂ ) _m NR-; L is an unsubstituted phenyl ring or halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxy of 1-6 carbon atoms Alkyl, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, tri of 1-6 carbon atoms Fluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 Alkylamino of 2 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, 3-8 Alkynylamino of carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, 2 -N-alkylaminoalkyl of 9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N of 3-10 carbon atoms, Phenyl ring mono-, di- or tri-substituted with a substituent selected from the group consisting of N-dialkylaminoalkoxy, mercapto and benzoylamino; Provided that L can be an unsubstituted phenyl ring only when m> 0 and T is not -CH ₂ NH- or -CH ₂ O-; L is a 5 or 6 membered heteroaryl ring, wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O and S, provided that the heteroaryl ring contains no OO, SS or SO bonds and the heteroaryl ring is Halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halo Methyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, trifluoromethyl of 1-6 carbon atoms , Cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbon atoms Alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkano of 1-6 carbon atoms Amino, alkenoylamino of 3-8 carbon atoms, alkinoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, 1-5 Aminoalkyl of carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, 3- Optionally mono- or di-substituted with a substituent selected from the group consisting of 10 carbon atoms of N, N-dialkylaminoalkoxy, mercapto and benzoylamino; Z is -NH-, -O-, -S- or -NR-; R is alkyl of 1-6 carbon atoms or carboalkyl of 2-7 carbon atoms; G ₁ , G ₂ , R ₁ and R ₄ are each independently hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, 2-6 Alkenyloxy of 2 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, 3- Alkynoyloxy of 8 carbon atoms, Alkanoyloxymethyl of 2-7 carbon atoms, Alkenoyloxymethyl of 4-9 carbon atoms, Alkynoyloxymethyl of 4-9 carbon atoms, 2-7 Alkoxymethyl of 1 carbon atom, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, 1- Alkylsulfonamido of 6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cya Rowing, Tro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxy of 1-4 carbon atoms Amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N of 4 to 12 carbon atoms Alkenylamino, N, N-dialkenylamino, phenylamino, benzylamino of 6-12 carbon atoms, Or; R ₁ and R ₄ are as described above and G ₁ or G ₂ or both are R ₂ -NH-; If the substituents R ₁ , G ₂ , G ₃ or R ₄ are located on adjacent carbon atoms they can be taken together as a _divalent radical -OC (R ₆ ) ₂ -O-; Y is A divalent radical selected from the group consisting of; R ₇ is —NR ₆ R ₆ , —OR ₆ , —J, —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ); M is> NR ₆ , -O-,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p -OR ₆ ; W is> NR ₆ , -O- or a bond; Het is morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S, S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran and It is selected from the group consisting of; Wherein Het is optionally mono- or di-substituted with R ₆ on carbon or nitrogen, hydroxy on carbon, —N (R ₆ ) ₂ or Optionally mono- or di-substituted with -OR ₆ and optionally mono with monovalent radicals-(C (R ₆ ) ₂ ) _s OR ₆ or-(C (R ₆ ) ₂ ) _s N (R ₆ ) ₂ on carbon Or di-substituted and optionally mono or di-substituted with a divalent radical —O— or —O (C (R ₆ ) ₂ ) _s O— on saturated carbon; R ₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, 2-7 carbon atoms Carboalkyl, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkyl of 1-3 carbon atoms Amino, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1-6 Alkylthio, hydroxy, carboxyl of carbon atoms, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoyl of 1-6 carbon atoms Amino or alkyl of 1-6 carbon atoms, provided that alkenyl or alkynyl moieties are provided with nitrogen or oxygen atoms via saturated carbon atoms. And the sum; R ₂ is selected from the group consisting of: R ₃ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₅ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₈ and R ₉ are, independently from each other, — (C (R ₆ ) ₂ ) _r NR ₆ R ₆ or — (C (R ₆ ) ₂ ) _r OR ₆ ; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl or hydrogen of 1-6 carbon atoms; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; m is 0-3; p = 2-4; q = 0-4; r = 1-4; s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; Provided that if R ₆ is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, these alkenyl or alkynyl moieties are bonded to nitrogen or oxygen atoms via saturated carbon atoms; Further, if Y is —NR ₆ — and R ₇ is —NR ₆ R ₆ , —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ), g = 2-6; When M is -O- and R ₇ is -OR _6, p = 1-4; If Y is —NR ₆ — then k = 2-4; When Y is -O- and M or W is -O-, k = 1-4; Q = 2-4 unless W is a bond to Het bonded via a nitrogen atom; If W is a bond to Het bonded through a nitrogen atom and Y is -O- or -NR ₆ -then k = 2-4. A pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. Formula 1 In the above formula, X is a bicyclic aryl or bicyclic heteroaryl ring system of 8 to 12 atoms, and the bicyclic heteroaryl ring contains 1 to 4 heteroatoms selected from N, O and S, provided that acyclic hetero The aryl ring does not contain OO, SS or SO bonds, and the bicyclic aryl or bicyclic heteroaryl rings are halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, 2 Alkynyl of 6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1- Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, carbo of 2-7 carbon atoms Alkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbons Of alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, of 3-8 carbon atoms Alkinoylamino, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, 3 -N, N-dialkylaminoalkyl of 10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy, mercapto and benzoylamino of 3-10 carbon atoms Optionally mono-, di-, tri- or tetra-substituted with a substituent selected from the group consisting of: X is a chemical formula Radicals wherein A is a pyridinyl, pyrimidinyl or phenyl ring; a pyridinyl, pyrimidinyl or phenyl ring is halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, Alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1 Alkoxy of 6 carbon atoms, alkylthio, hydroxy, trifluoromethyl, cyano, nitro, carboxy of 1-6 carbon atoms, carboalkoxy of 2-7 carbon atoms, of 2-7 carbon atoms Carboalkyl, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, 1-6 Alkanoylamino of carbon atom, Alkenoylamino of 3-8 carbon atoms, Alkynoylamino of 3-8 carbon atoms, 2-7 carbons Carboxyalkyl of atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N- of 3-10 carbon atoms Optionally mono- or substituted with a substituent selected from the group consisting of dialkylaminoalkyl, N-alkylaminoalkoxy of 2-9 carbon atoms, N, N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto and benzoylamino Di-substituted; T is bonded to the carbon of A and -NH (CH ₂ ) _m- , -O (CH ₂ ) _m- , -S (CH ₂ ) _m- , -NR (CH ₂ ) _m -,-(CH ₂ ) _m -,-(CH ₂ ) _m NH-,-(CH ₂ ) _m O-,-(CH ₂ ) _m S- or-(CH ₂ ) _m NR-; L is an unsubstituted phenyl ring or halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxy of 1-6 carbon atoms Alkyl, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, tri of 1-6 carbon atoms Fluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 Alkylamino of 2 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, 3-8 Alkynylamino of carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N of 3-10 carbon atoms , Is a phenyl ring mono-, di- or tri-substituted with a substituent selected from the group consisting of N-dialkylaminoalkoxy, mercapto and benzoylamino; Provided that L can be an unsubstituted phenyl ring only when m> 0 and T is not -CH ₂ NH- or -CH ₂ O-; L is a 5 or 6 membered heteroaryl ring, wherein the heteroaryl ring contains 1 to 3 heteroatoms selected from N, O and S, provided that the heteroaryl ring contains no OO, SS or SO bonds and the heteroaryl ring is Halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halo Methyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio, hydroxy, trifluoromethyl of 1-6 carbon atoms , Cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, 1-6 carbon atoms Alkylamino, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkano of 1-6 carbon atoms Amino, alkenoylamino of 3-8 carbon atoms, alkinoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, 1-5 Aminoalkyl of carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N, N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, 3- Optionally mono- or di-substituted with a substituent selected from the group consisting of 10 carbon atoms of N, N-dialkylaminoalkoxy, mercapto and benzoylamino; Z is -NH-, -O-, -S- or -NR-; R is alkyl of 1-6 carbon atoms or carboalkyl of 2-7 carbon atoms; G ₁ , G ₂ , R ₁ and R ₄ are each independently hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, 2-6 Alkenyloxy of 2 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, 3- Alkynoyloxy of 8 carbon atoms, Alkanoyloxymethyl of 2-7 carbon atoms, Alkenoyloxymethyl of 4-9 carbon atoms, Alkynoyloxymethyl of 4-9 carbon atoms, 2-7 Alkoxymethyl of 1 carbon atom, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulfinyl of 1-6 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, 1- Alkylsulfonamido of 6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cya Rowing, Tro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxy of 1-4 carbon atoms Amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N, N-dialkylcarbamoyl, N-alkyl-N of 4 to 12 carbon atoms Alkenylamino, N, N-dialkenylamino, phenylamino, benzylamino of 6-12 carbon atoms, Or; R ₁ and R ₄ are as described above and G ₁ or G ₂ or both are R ₂ -NH-; If the substituents R ₁ , G ₂ , G ₃ or R ₄ are located on adjacent carbon atoms they can be taken together as a _divalent radical -OC (R ₆ ) ₂ -O-; Y is A divalent radical selected from the group consisting of; R ₇ is —NR ₆ R ₆ , —OR ₆ , —J, —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ); M is> NR ₆ , -O-,> N- (C (R ₆ ) ₂ ) _p NR ₆ R ₆ or> N- (C (R ₆ ) ₂ ) _p -OR ₆ ; W is> NR ₆ , -O- or a bond; Het is morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S, S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran and It is selected from the group consisting of; Wherein Het is optionally mono- or di-substituted with R ₆ on carbon or nitrogen, hydroxy on carbon, —N (R ₆ ) ₂ or Optionally mono- or di-substituted with -OR ₆ and optionally mono with monovalent radicals-(C (R ₆ ) ₂ ) _s OR ₆ or-(C (R ₆ ) ₂ ) _s N (R ₆ ) ₂ on carbon Or di-substituted and optionally mono or di-substituted with a divalent radical —O— or —O (C (R ₆ ) ₂ ) _s O— on saturated carbon; R ₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, 2-7 carbon atoms Carboalkyl, carboxyalkyl (2-7 carbon atoms), phenyl or phenyl optionally substituted with one or more halogens, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkyl of 1-3 carbon atoms Amino, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, 1-6 Alkylthio, hydroxy, carboxyl of carbon atoms, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoyl of 1-6 carbon atoms Amino or alkyl of 1-6 carbon atoms, provided that alkenyl or alkynyl moieties are provided with nitrogen or oxygen atoms via saturated carbon atoms. And the sum; R ₂ is selected from the group consisting of: R ₃ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₅ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, Is; R ₈ and R ₉ are, independently from each other, — (C (R ₆ ) ₂ ) _r NR ₆ R ₆ or — (C (R ₆ ) ₂ ) _r OR ₆ ; J is independently hydrogen, chlorine, fluorine or bromine; Q is alkyl or hydrogen of 1-6 carbon atoms; a = 0 or 1; g = 1-6; k = 0-4; n is 0-1; m is 0-3; p = 2-4; q = 0-4; r = 1-4; s = 1-6; u = 0-4 and v = 0-4, where the sum of u + v is 2-4; Provided that if R ₆ is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, these alkenyl or alkynyl moieties are bonded to nitrogen or oxygen atoms via saturated carbon atoms; Further, if Y is —NR ₆ — and R ₇ is —NR ₆ R ₆ , —N (R ₆ ) ₃ ⁺ or —NR ₆ (OR ₆ ), g = 2-6; When M is -O- and R ₇ is -OR _6, p = 1-4; If Y is —NR ₆ — then k = 2-4; When Y is -O- and M or W is -O-, k = 1-4; Q = 2-4 unless W is a bond to Het bonded via a nitrogen atom; If W is a bond to Het bonded through a nitrogen atom and Y is -O- or -NR ₆ -then k = 2-4. (a) converting an aminocarbonyl group to a cyano group by reacting a compound of formula (b) a compound of Formula A ₁ -NH-A ₂ or a salt thereof is represented by Formula QA ₃ , wherein Q is a leaving group and A ₁ , A ₂ and A ₃ are A ₁ -NA ₂ -A ₃ To match the compound), or (c) a compound of formula A ₄ -OH, or a salt thereof, wherein the compound of formula QA ₅ , wherein Q is as defined above and A ₄ and A ₅ allow A ₄ -OA ₅ to match the compound of formula 1 React with; (d) adding an acid to the compound of formula 1 to produce an acid addition salt. 18. A process for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof. Chemical formula In the above formula, R ₁ , G ₁ , G ₂ , R ₄ , Z, n and X are as described above.